Effectiveness and Safety of the MVA-BN Vaccine against Mpox in At-Risk Individuals in the United States (USMVAc).

The mpox 2022 outbreak was declared a public health emergency in July 2022. In August 2022, the MVA-BN vaccine received emergency use authorization in the United States (US) to target at-risk groups. This study (EUPAS104386) used HealthVerity's administrative US healthcare data to generate real-world evidence for MVA-BN vaccine effectiveness and safety to prevent mpox disease in men who have sex with men (MSM) and transgender women, the most affected population during the 2022 mpox outbreak. Fully vaccinated subjects (two doses ≥ 28 days apart) were initially matched with five unvaccinated subjects on calendar date, age, US region, and insurance type. Subjects were followed from index date (14 days after the second dose) until death or data end to ascertain mpox occurrence. After propensity score adjustment, the MVA-BN vaccine effectiveness against mpox disease was 89% (95% CI: 12%, 99%) among those fully vaccinated; attenuated to 64% (95% CI: 40%, 78%) among those with any dose and 70% (95% CI: 44%, 84%) for those with only a single dose. One pericarditis adverse event of special interest was observed when the risk window was extended to 28 days. These results contribute to the totality of evidence supporting the favorable benefit/risk profile of the MVA-BN vaccine.

Uncontrolled blood pressure and therapeutic inertia in treated hypertensive patients: A retrospective cohort study using a UK general practice database.

Uncontrolled blood pressure (BP) and therapeutic inertia pose significant challenges in effectively managing hypertension. This study objective was to quantify levels of uncontrolled BP and therapeutic inertia among patients treated for hypertension in primary care. This retrospective cohort study used data recorded by general practitioners from the UK Clinical Practice Research Datalink database. Adults with primary hypertension who received a recorded prescription for any antihypertensive drug between January 2015 and June 2017 (index date) were included, with a follow-up of 18 months. Primary outcomes included the percentage of patients with uncontrolled BP (defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and of apparent therapeutic inertia (defined as two consecutive uncontrolled BP records without treatment change) during follow-up. Finally, of 581 260 patients receiving antihypertensive drug(s), 37.2% (n = 216 014) had uncontrolled BP at the index date and 30.3% (n = 175 955) had no record of BP at this date. During follow-up, 59.2% had ≥1 record of uncontrolled BP, in 22% all records showed uncontrolled BP, and 12.8% had no record of BP. Among those with uncontrolled BP at the index date, 72.9% had ≥1 record of uncontrolled BP during follow-up, and in 28.3% all records showed uncontrolled BP. Therapeutic inertia was observed in 33.1% of patients overall, and in 55.7% of those with uncontrolled BP at the index date. In conclusion, BP recording was infrequent, possibly reflecting both a low frequency of measurement and potential under-recording. Uncontrolled BP and therapeutic inertia appear to be widespread in UK general practice.

A Case for Synthetic Data in Regulatory Decision-Making in Europe.

Regulators are faced with many challenges surrounding health data usage, including privacy, fragmentation, validity, and generalizability, especially in the European Union, for which synthetic data may provide innovative solutions. Synthetic data, defined as data artificially generated rather than captured in the real world, are increasingly being used for healthcare research purposes as a proxy to real-world data (RWD). Currently, there are barriers particularly challenging in Europe, where sharing patient's data is strictly regulated, costly, and time-consuming, causing delays in evidence generation and regulatory approvals. Recent initiatives are encouraging the use of synthetic data in regulatory decision making and health technology assessment to overcome these challenges, but synthetic data have still to overcome realistic obstacles before their adoption by researchers and regulators in Europe. Thus, the emerging use of RWD and synthetic data by pharmaceutical and medical device industries calls regulatory bodies to provide a framework for proper evidence generation and informed regulatory decision making. As the provision of data becomes more ubiquitous in scientific research, so will innovations in artificial intelligence, machine learning, and generation of synthetic data, making the exploration and intricacies of this topic all the more important and timely. In this review, we discuss the potential merits and challenges of synthetic data in the context of decision making in the European regulatory environment. We explore the current uses of synthetic data and ongoing initiatives, the value of synthetic data for regulatory purposes, and realistic barriers to the adoption of synthetic data in healthcare.

Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes.

AIMS: To compare the effectiveness and safety of gliclazide modified release (MR) to sitagliptin as type 2 diabetes mellitus (T2D) treatments in a real-world patient population. MATERIALS AND METHODS: This retrospective cohort study used records from the UK Clinical Practice Research Datalink. The cohort consisted of adult patients with T2D newly treated with either gliclazide MR or sitagliptin as second-line treatment added to metformin and with a glycated haemoglobin (HbA1c) level of ≥7.0% (53 mmol/mol). Patients were 1:1 matched using high-dimensional propensity score matching and followed to determine the time taken to reach an HbA1c <7.0%. Secondary outcomes included time to HbA1c ≤6.5% (48 mmol/mol), time to ≥1% (11 mmol/mol) HbA1c reduction from baseline, treatment persistence and durability, and hypoglycaemic events. RESULTS: Among the 1986 patients included, those on gliclazide MR more likely achieved an HbA1c <7.0% [hazard ratio (HR): 1.35; 95% confidence interval (CI): 1.15-1.57], HbA1c ≤6.5% (HR: 1.51; 95% CI: 1.19-1.92) or had an HbA1c reduction ≥1% from baseline (HR: 1.11; 95% CI: 1.00-1.24) compared with patients on sitagliptin. Durability (log-rank P = .135) and persistence (P = .119) were similar between the two groups. Hypoglycaemic events were uncommon (23 total severe and non-severe events; incidence rate, 3.7 per 1000 patient years), with 4.7 and 2.6 events per 1000 patient years with gliclazide MR and sitagliptin treatment, respectively. CONCLUSIONS: In this real-world study, second-line gliclazide MR was more effective than sitagliptin in reducing HbA1c, with similar durability and persistence and low rates of hypoglycaemic events, in individuals with T2D on metformin treatment and HbA1c above the target of 7.0%.

Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk-minimization measures.

PURPOSE: This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study. METHODS: This was a multinational (five European countries) chart review study with two study periods: pre-RMM and post-RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow-up, and no concomitant use of verapamil or diltiazem. RESULTS: Overall, 711 and 506 eligible patients were included in the pre-RMM and post-RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post-RMM period (70.6% and 78.4% in the pre- and post-RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow-up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007). CONCLUSIONS: The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris.

Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany.

PURPOSE: Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). METHODS: Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. RESULTS: On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. CONCLUSIONS: In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.

Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

PURPOSE: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). METHODS: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. RESULTS: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark. CONCLUSIONS: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

BACKGROUND: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden. METHODS: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. RESULTS: Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. LIMITATIONS: The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. CONCLUSIONS: Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.

Agomelatine Drug Utilisation Study in Selected European Countries: A Multinational, Observational Study to Assess Effectiveness of Risk-Minimisation Measures.

BACKGROUND: Hepatotoxic reactions are an important identified risk listed in the agomelatine risk management plan. This post-authorisation safety study evaluated the effectiveness of additional risk-minimisation measures (aRMMs) for agomelatine. OBJECTIVE: The objective of this study was to evaluate, among physicians prescribing agomelatine and their patients, liver function monitoring adherence, compliance with contraindications and patients' reasons for non-compliance with liver monitoring. METHODS: A non-interventional cohort study was conducted among adults initiating agomelatine in routine clinical practice in Denmark, France, Germany and Spain through a retrospective medical record abstraction (MRA) before and after implementation of aRMMs and a cross-sectional patient survey. RESULTS: Fifty-four sites contributed data on 437 and 404 patients in the before- and after-RMM periods, and 237 patients completed the survey. No patient had cirrhosis in either study period; 98.2% of patients in the before- and 98.0% in the after-RMM period had no active liver disease reported at initiation or during treatment. Compliance to contraindicated medications was > 99% in both periods. The adherence to the liver-monitoring regimen was similar in both periods (15.1% before RMM and 16.3% after RMM). In the after-RMM period, 25.2% of patients had a liver test before or at treatment initiation; 61.5% had a liver test during treatment. Among patients surveyed who did not have a blood test before treatment initiation or during treatment, the most frequently cited reason was a test ordered but not yet performed. CONCLUSIONS: The overall adherence to liver-monitoring recommendations remained weakly influenced by aRMMs. However, patients treated with agomelatine are in compliance with relevant contraindications.