Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies.

In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81-10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9-18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2-14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

Time-Trends of Drug-Drug Interactions among Elderly Outpatients in the Piedmont Region (Italy): A Population-Based Study.

Adverse drug reactions (ADRs) are a major health problem in the primary care setting, particularly among the elderly population. While the high frequency of ADRs in the elderly has several causes, a major and common determinant is polypharmacy, which can in turn increase the risk of drug-drug interactions (DDIs). In this paper, we analyzed the drugs prescriptions dispensed to elderly outpatients, to assess changes in the prevalence of selected DDIs in the period 2013−2019. Overall, about 15% of the patients aged >65 years were poly-treated. Among them, a decreasing trend in prevalence was observed for the majority of DDIs during the study period. This trend was particularly noticeable for DDIs involving fluoroquinolones and vitamin K antagonists, where a sharp reduction of over 40% was observed. On the opposite, a small increase in prevalence was observed for the association of antidiabetics and beta-blocking agents and for that of clopidogrel and PPIs. While the occurrence of most of the considered DDIs among poly-treated elderly decreased over time, the prevalence of some of them is still worrying. The complexity of the national drug formularies, as well as the increased number of prescribing actors that are involved, further urges the update of DDI lists to be used to monitor drug appropriateness and reduce avoidable ADRs.

Potentially Inappropriate Prescribing among Elderly Outpatients: Evaluation of Temporal Trends 2012-2018 in Piedmont, Italy.

Pharmacological intervention is one of the cornerstones in the treatment and prevention of disease in modern healthcare. However, a large number of drugs are often prescribed and used inappropriately, especially in elderly patients. We aimed at investigating the annual prevalence of potentially inappropriate prescriptions (PIPs) among older outpatients using administrative healthcare databases of the Piedmont Region (Italy) over a seven-year period (2012-2018). We included all Piedmont outpatients aged 65 years or older with at least one drug prescription per year. Polypharmacy and the prevalence of PIPs according to the ERD list explicit tool were measured on an annual basis. A range between 976,398 (in 2012) and 1,066,389 (in 2018) elderly were evaluated. Among them, the number of subjects with at least one PIP decreased from 418,537 in 2012 to 339,764 in 2018; the prevalence significantly reduced by ~25% over the study period. The stratified analyses by age groups and sex also confirmed the downward trend and identified several differences in the most prevalent inappropriately prescribed drugs. Overall, despite a reduction in PIP prevalence, one out of three older outpatients was still exposed to inappropriateness, highlighting the extensive need for intervention to improve prescribing.

Use of State Sequence Analysis in Pharmacoepidemiology: A Tutorial.

While state sequence analysis (SSA) has been long used in social sciences, its use in pharmacoepidemiology is still in its infancy. Indeed, this technique is relatively easy to use, and its intrinsic visual nature may help investigators to untangle the latent information within prescription data, facilitating the individuation of specific patterns and possible inappropriate use of medications. In this paper, we provide an educational primer of the most important learning concepts and methods of SSA, including measurement of dissimilarities between sequences, the application of clustering methods to identify sequence patterns, the use of complexity measures for sequence patterns, the graphical visualization of sequences, and the use of SSA in predictive models. As a worked example, we present an application of SSA to opioid prescription patterns in patients with non-cancer pain, using real-world data from Italy. We show how SSA allows the identification of patterns in prescriptions in these data that might not be evident using standard statistical approaches and how these patterns are associated with future discontinuation of opioid therapy.

Methimazole Treatment and Risk of Acute Pancreatitis: A Population-based Cohort Study.

CONTEXT: A warning has been recently issued by the European Medicine Agency (EMA) regarding a potential increased risk of acute pancreatitis (AP) in methimazole (MMI) users. OBJECTIVE: To investigate the association between MMI and the diagnosis of AP in a population-based study. MATERIALS AND METHODS: A retrospective analysis of administrative health databases was conducted (2013-2018). Relevant data were obtained from: (1) inhabitants registry, (2) hospital discharge records (ICD-9-CM 577.0), and (3) drug claims registry (ATC H03BB02). We evaluated AP risk in MMI users in 18 months of treatment, stratifying results by trimester. Poisson regression was used to estimate the age- and sex-adjusted rate ratios (RR), and the relative 95% confidence intervals (CI), comparing rates of AP between MMI users and nonusers. The absolute risk of AP in MMI users was also calculated. RESULTS: A total of 23 087 new users of MMI were identified. Among them, 61 hospitalizations occurred during the study period. An increase in AP risk was evident during the first 3 trimesters of therapy (RR 3.40 [95% CI: 2.12-5.48]; RR 2.40 [95% CI: 1.36-4.23]; RR 2.80 [95% CI: 1.66-4.73]), but disappeared thereafter. The AP absolute risk in MMI users during the first 18 months of treatment was less than 0.4% in all sex and age classes. CONCLUSIONS: Our results support the EMA warning, suggesting an increased risk of AP associated with MMI use. However, such an increase seems limited to the first months of MMI treatment. Moreover, in absolute terms, the probability of AP is low among patients, well below 1%.

Incidence and prevalence of hyperthyroidism: a population-based study in the Piedmont Region, Italy.

PURPOSE: Unrecognized and untreated hyperthyroidism leads to serious clinical complications with adverse outcomes for patients and increasing costs for the health care system. Hence, adequate knowledge of the epidemiological features of such condition is desirable to plan effective interventions. The aim of our study was to estimate incidence and prevalence of hyperthyroidism in the mildly iodine-deficient Italian Region of Piedmont. METHODS: A retrospective cohort study was conducted using Administrative Health Databases of the Piedmont Region, Italy (2012-2018). Hyperthyroidism cases were defined as the subjects who had at least one of the following claims: (i) hospital discharge records with hyperthyroidism diagnosis code; (ii) exemption from co-payment for hyperthyroidism; (iii) prescription of one of the following medications: methimazole, propylthiouracil, or potassium perchlorate. RESULTS: The overall prevalence was 756 per 100,000 inhabitants [95% CI 748-764], and the overall incidence was 81 per 100,000-person year [95% CI 80-82]. The prevalence and incidence increased with age and were two-fold higher among women than men. Women also showed two distinct peaks in incidence at the age of 30 and 50; after the age of 60, the trend became similar between sexes. With regard to the geographic distribution, an increasing gradient of incidence was observed from the northern to the south-western areas of the Region. CONCLUSION: This is the first Italian study based on health databases to estimate the incidence and prevalence of hyperthyroidism in the general population. This approach can represent an inexpensive and simple method to monitor patterns of hyperthyroidism in iodine-deficient areas.