Observational studies have evaluated the risk of acute pancreatitis associated with drugs acting on the Renin-Angiotensin-Aldosterone System (RAAS) but reported conflicting results. This meta-analysis aims to investigate the risk of acute pancreatitis associated with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). PubMed and Embase were searched for observational studies. A random-effects model was used to pool odds ratios (ORs). A sensitivity analysis explored the robustness of the initial findings according to study design, treatment duration, dose, age, active substance, and Risk of Bias scores. Main results were re-analyzed using the Knapp-Hartung method and Bayesian random-effects. Eleven observational studies were included. ACE inhibitors increased the risk of acute pancreatitis (OR 1.33; 95% CI 1.12-1.58; I² = 93%), whereas ARBs did not (OR 0.82; 95% CI 0.80-0.83; I² = 0%). Few studies presented disaggregated results for the sensitivity analyses, but most estimates were consistent with the initial findings. The Knapp-Hartung method and Bayesian random-effects meta-analyses yielded similar results. The incidence rate of acute pancreatitis among patients treated with ACE inhibitors was 0.98 cases per 1,000 person-years, while for ARBs it was 0.71 cases per 1,000 person-years. These results suggest that ACE inhibitors increase the risk of acute pancreatitis, in contrast to the effect of ARBs. Healthcare professionals should be aware of the potential risk of pancreatitis when managing patients receiving these medications.

Background:COVID-19 vaccination is still accepted by only half of pregnant women. Further scientific evidence on the safety of the COVID-19 vaccine could help overcome vaccine hesitancy in this population. Objectives:The aim of this study is to describe and compare the incidence of solicited and unsolicited adverse drug reactions (ADRs) and serious adverse reactions following the booster dose of different COVID-19 vaccines in pregnant women versus the general female population. Methods:We conducted a web-based prospective observational cohort study. In eight European countries, pregnant women and non-pregnant women from the same source population who received a first or second booster dose of COVID-19 vaccine between February 2021 and February 2023 were included in the study if they registered within 48 h after vaccination and completed at least the baseline questionnaire and one follow-up questionnaire. The exposure was a mRNA COVID-19 vaccine of different brands used for a booster dose. The proportion of solicited and unsolicited ADRs following the booster dose by vaccine brand was computed across participating countries in pregnant and non-pregnant women. We performed descriptive analyses of medical characteristics of vaccinees. We compared the proportions of local and systemic solicited ADRs and unsolicited ADRs in pregnant vaccinees with a random sample (1:4 ratio) of age- and vaccine brand-matched vaccinees from the general female population. Results:Overall, 358 pregnant women were matched with 1,432 women from the general population. The proportion of women who reported at least one solicited adverse event was significantly lower in the pregnant group in the non-pregnant group (56.4% [95%CI 51.3%-61.5%] versus 72.3% [95%CI 70.0%-74.6%], p = 0.01). Regarding local ADRs, pregnant women reported significantly less pain and swelling. As for systemic ADRs, pregnant women reported all symptoms less frequently than non-pregnant women, except nausea. The proportion of women who reported at least one unsolicited adverse event was less frequent in the pregnant group (7.8% [95%CI 5.0%-10.6%] versus 24.9% [95%CI 22.7%-27.1%], p = 3.10-10). Serious adverse events were reported in 0.8% and 0.3% of pregnant and non-pregnant women respectively. Conclusion:This prospective study on COVID-19 vaccine safety monitoring showed that pregnant women from the general population reported solicited and unsolicited ADRs less frequently than non-pregnant women.

INTRODUCTION AND OBJECTIVES:This study aimed to evaluate the impact of the COVID-19 pandemic on healthcare provided to patients with arterial hypertension in Portugal. METHODS:The pre-pandemic and pandemic periods were compared using publicly available data on performance and health outcome indicators from the Portuguese National Health Service (NHS). Pre-pandemic data were modeled to project hypothetical scenarios without a pandemic using an exponential smoothing algorithm, and then compared with data collected during the COVID-19 pandemic. A cohort model was developed to estimate the number of all-cause deaths and years of life lost (YLL) due to the reduction in blood pressure (BP) monitoring and in BP records <150/90 mmHg during the first two years of the pandemic. Microsoft Excel® was used for statistical analyses. RESULTS:There was a 26.4% relative reduction in the number of patients with hypertension under 65 years of age with at least one BP measurement, and a 21.8% relative reduction in the proportion of patients with BP <150/90 mmHg during the first two years of the pandemic. The model projections were 176 additional deaths and 3287 YLL among the Portuguese population of patients with hypertension. CONCLUSIONS:The disruption in BP testing in Portugal during the pandemic increased hypertension-associated morbidity and mortality, with significant YLL. The long-term implications of impaired monitoring of patients with hypertension should be assessed, and proactive strategies implemented to mitigate the increase in hypertension morbidity and mortality associated with the COVID-19 pandemic.

BackgroundAccording to international research, an increase in the patient share of pharmaceutical expenditure results in a decrease in medicines utilization. In 2010, the Portuguese government reduced the reimbursement rate for certain therapeutic classes. The aim of this study was to evaluate the impact of raising cost to the patient on the utilization of medicines.MethodsBetween January 1996 and December 2015, medicines utilization and cost to the patient per DDD of antihypertensive, antidyslipidemic, antidiabetic, antiulcer and antidepressant medicines were compared. A segmented linear regression of two time series - before and after the change in reimbursement percentage - was used.ResultsDuring the two time series, there was an increase in the utilization of antidepressants and antiulcer medicines. The consumption growth decelerated following the reduction in reimbursement rate. Cost to the patient decreased for both classes across the two time series, although the trend accelerated during the second.ConclusionThese findings suggest that a decrease in the reimbursement rate had little impact on the utilization of medicines. It is reasonable to assume that the reduction in percentage covered by the Portuguese National Health System was gradually compensated by the decrease in the absolute amount that patients paid for medicines..

Background Cervical cancer is a major concern to women’s health, being the fourth most common cancer worldwide. A great percentage of these cancer is consequence of an HPV infection, namely from specific genotypes such as 16/18. Portuguese screening program subjects women to a reflex cytology triage every 5 years. Aptima® HPV is a screening test which presents better specificity than other tests which are used in Portugal (Hybrid Capture® 2 and Cobas® 4800) and still have a comparable sensitivity. The present study aims to estimate the number of diagnostic tests and costs that are avoided using Aptima® HPV compared to the use of two other tests, Hybrid Capture® 2 and Cobas® 4800, within the cervical cancer screening programme in Portugal. Methods A model, consisting of a decision-tree, was developed to represent the full Portuguese screening program for cervical cancer. This model is used to compare the costs resulting from using Aptima® HPV test versus the other tests used in Portugal, during 2 years. Other outcomes such as the number of additional tests and exams were also computed. This comparison considers the performance of each test (sensitivity and specificity) and assumes an equal price for every test compared. Results Cost savings resulting from the use of Aptima® HPV are estimated at approximately €382 million versus Hybrid Capture® 2 and €2.8 million versus Cobas® 4800. Moreover, Aptima® HPV prevents 265,443 and 269,856 additional tests and exams when compared with Hybrid Capture® 2 and Cobas® 4800. Conclusions The use of Aptima® HPV resulted in lower costs as well as less additional test and exams. These values result from the greater specificity of Aptima® HPV, which signals less false positive cases and consequently avoids carrying out additional tests.

INTRODUCTION:Potential associations between Chronic Obstructive Pulmonary Disease (COPD) and osteoporosis have been studied, but areas of uncertainty remain. OBJECTIVE:This scoping review aimed to identify the published evidence on the epidemiological relationships between COPD and osteoporosis. METHODS:Experimental and observational evidence evaluating relationships between COPD and osteoporosis on epidemiology, clinical manifestations, risk factors (RFs), therapeutic management and quality of life (QoL) was searched on PubMed and Embase (until May 2023). The studies were categorized according to their objectives and characteristics. Data were analyzed using descriptive statistics. RESULTS:Ninety-nine studies were selected, namely 33 (33%) reporting epidemiologic measures, 11 (11%) clinical manifestations, 74 (75%) RFs (45 ones, of which body mass index [BMI; n = 22 studies], corticosteroids' use [n = 20], and COPD severity [n = 15] were the most studied), 7 (7%) therapeutic management, and 3 (3%) QoL. Twenty-seven (27.6%) studies evaluated ≥2 domains. Most studies followed a cross-sectional design (n = 37; 37.4%). Eighty-nine studies (90%) assessed patients with COPD at baseline and studied its relationship with osteoporosis. CONCLUSION:There are well-established features linking COPD and osteoporosis, including shared RFs, such as smoking, elderly, physical inactivity, or low BMI. Others deserve clarification, including the impact of COPD severity, or the use of inhaled corticosteroids on the incidence of osteoporosis and fractures, as well as the value of performing routine imaging tests, or prescribing anti-resorptive medications in COPD to prevent osteoporotic-related outcomes. QoL studies are also lacking. Investigating such issues is needed to propose clinical guidelines for managing osteoporosis in patients with COPD.

Background: Conventional vaccines rarely cause severe allergic reactions. However, the rapid development and approval of COVID-19 vaccines left limited initial data on their adverse reactions, particularly in individuals with a history of allergy. The aim of this study was to assess and compare the safety profile of different doses and brands of COVID-19 vaccines in subjects with a history of allergy vs. those without a history of allergy. Methods: From February 2021 to February 2023, a web-based prospective study gathered vaccinee-reported outcomes using electronic questionnaires across eleven European countries. Baseline and up to six follow-up questionnaires captured data on vaccinee demographics, as well as both solicited and unsolicited adverse reactions. Results: Overall, 3476 vaccinees with a history of allergy were matched with 13,872 vaccinees from the general population at the first vaccination cycle and were included in the analysis. A total of 825 vaccinees with a history of allergy who had received a booster dose, matched to 3297 vaccinees from the general population, were included in the analysis. Higher rates of ADRs occurred after the first vaccination cycle compared to after the booster dose (64–91% vs. 56–79%). However, most reported ADRs were solicited and not serious, and no case of anaphylaxis was reported. Women and vaccinees with a history of allergy reported ADRs more frequently than men and the matched controls, respectively. Compared to other COVID-19 vaccines, a higher proportion of vaccinees experiencing at least one ADR following their first vaccination cycle was observed with Comirnaty and Vaxzevria. Statistically significant differences were observed among the study cohorts for median TTO after the second dose, and for median TTR following the first vaccination cycle and booster dose (p < 0.001). Conclusions: Typically, any drug or vaccine use carries a risk of severe allergic reactions, yet the benefits of vaccination generally outweigh these potential risks, as shown with the COVID-19 vaccines.

BACKGROUND:The safety profile of COVID-19 vaccines in immunocompromised patients has not been comprehensively evaluated. AIM:To measure the frequency of patient-reported adverse drug reactions (ADRs) related to the first/second/booster dose of COVID-19 vaccine in immunocompromised subject versus matched cohort. As a secondary objective, the time course, evaluated as time to onset (TTO) and time to recovery (TTR), of COVID-19 vaccine-related ADRs was explored. METHODS:A prospective cohort study, based on electronic questionnaires filled by vaccinees from 11 European countries in the period February 2021 to February 2023 was conducted. All immunocompromised vaccinees who provided informed consent and registered to the project's web-app within 48 h after first/booster vaccine dose administration of any EMA-authorised COVID-19 vaccine were recruited. Participants filled baseline and up to six follow-up questionnaires (FU-Qs) over 6 months from vaccination, collecting information on suspected COVID-19 vaccine-related ADRs. As a control group, non-immunocompromised vaccinees from the same source population were 1:4 matched by sex, age, vaccine dose, and brand. A descriptive analysis of demographic/clinical characteristics of vaccinees was conducted. Heatmaps of the frequency of solicited ADRs, stratified by gender and vaccine brand, were generated. Median TTO/TTR of reported ADRs were visualised using violin/box-plots. RESULTS:A total of 773 immunocompromised vaccines were included in the analyses. Most participants were females (F/M ratio: 2.1 and 1.6) with a median age of 56 (43-74) and 51 (41-60) years, at the first vaccination cycle and booster dose, respectively. Injection-site pain and fatigue were the most frequently reported ADRs in immunocompromised vaccinees with higher frequency than matched control, especially after the first dose (41.2% vs 37.8% and 38.2% vs 32.9%, respectively). For both cohorts, all solicited ADRs were more frequently reported in females than males, and in those who had received a first dose of the Vaxzevria vaccine. Dizziness was the most frequently reported unsolicited ADR after the first dose in both groups (immunocompromised subjects: 2.5% and matched controls: 2.1%). At the booster dose, lymphadenopathy (3.9%) and lymphadenitis (1.8%) were the most reported unsolicited ADRs for immunocompromised subjects and matched controls, respectively. A very low number of subjects reported adverse event of special interest (AESI) (2 immunocompromised, 3 matched controls) and serious ADRs (5 immunocompromised, 5 matched controls). A statistically significant difference among study cohorts was observed for median TTO after the booster dose, and for median TTR after the first vaccination cycle and booster dose (p < 0.001). CONCLUSION:The overall safety profile of COVID-19 vaccines in immunocompromised people was favourable, with minor differences as compared to non-immunocompromised vaccinees. Participants mostly experienced mild ADRs, mainly reported after the first dose of Vaxzevria and Jcovden vaccines. Serious ADRs and AESI were rare.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). Results: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82 -74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient 's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19 --0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Conclusion: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real -time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

O Regulamento (UE) 2021/2282 do Parlamento Europeu e do Conselho, de 15 de dezembro de 2021, relativo à Avaliação de Tecnologias de Saúde (ATS) será aplicado a partir de 12 de janeiro de 2025, com o objetivo de auxiliar os países da União a avaliar a efetividade relativa das novas tecnologias de saúde em processos de solicitação de financiamento por terceiras entidades pagadoras, designadamente públicas. Face à implementação do regulamento europeu de ATS, é necessário e oportuno discutir as suas implicações na avaliação terapêutica e na avaliação económica de medicamentos, assim como as adaptações que poderão ocorrer nas estruturas de acesso ao mercado da indústria farmacêutica. Neste artigo relatam-se os resultados de uma discussão entre profissionais do acesso ao mercado, no sentido de perspetivar as implicações que o regulamento trará para o modelo local de avaliação farmacoterapêutica, avaliação económica, financiamento e acesso ao mercado de medicamentos, para a organização funcional e estrutural da indústria farmacêutica, bem como fornecer uma perspetiva global sobre o impacto do regulamento na Europa e em Portugal, com a identificação de cinco potenciais vantagens e cinco potenciais desvantagens associadas à sua aplicação na prática. Em conclusão, o regulamento europeu incide apenas sobre avaliação farmacoterapêutica, não constituindo uma abordagem transversal sobre a ATS. Este constitui uma oportunidade para tornar o modelo de avaliação farmacoterapêutica mais consistente entre os Estados-Membros e acelerar o acesso dos doentes à inovação. Não obstante, o regulamento não é vinculativo, carece de especificidade e mantém a independência dos Estados-Membros na tomada de decisão sobre o valor terapêutico das tecnologias de saúde.

Background Ibandronate is effective in reducing the risk of vertebral fractures, but experimental evidence offers conflicting results regarding nonvertebral fractures. Real-world evidence has been published evaluating the anti-nonvertebral fracture effect of ibandronate. Aim This meta-analysis of observational studies assessed the effectiveness of ibandronate in reducing the risk of nonvertebral fractures in women with osteoporosis. Method Pubmed/Embase databases were searched for observational studies. Risks of nonvertebral fractures and hip fractures were the outcomes. Meta-analyses were performed pooling rate ratios (RRs), using random-effects models. Data were reanalysed in sensitivity analyses considering Knapp–Hartung method and Bayesian random-effects. Results Six cohort studies were included. Overall, once-monthly 150 mg oral ibandronate reduced the risk of nonvertebral fractures (RR 0.84; 95% CI 0.76–0.94). Similar results were obtained when the comparison was restricted to once-monthly 150 mg risedronate, but no differences were found when the comparator was other oral bisphosphonates (weekly alendronate/risedronate). Ibandronate didn’t significantly change the risk of hip fractures (RR 1.25; 95% CI 0.89–1.76). The risk of hip fracture was comparable between once monthly, 150 mg oral ibandronate and other oral bisphosphonates. Intravenous ibandronate was not effective in reducing hip fractures comparing to intravenous zoledronate. The low number of studies diminished the robustness of sensitivity analyses. Conclusion Results suggest that once-monthly 150 mg oral ibandronate may be as effective as other oral bisphosphonates in reducing the risk of nonvertebral fractures. However, uncertainty associated to the small number of included studies, which are characterized by heterogeneous demographics and methodologies, precluded definitive conclusions.

Background: A rise in pharmaceutical expenses in Portugal led to the introduction of policy measures aimed at controlling outpatient public costs. This research examines and categorizes the most common pharmaceutical measures implemented during the Troika intervention, as well as comparing this period of time to prior ones. Methods: A hierarchical structure of descriptors was built to classify and group measures over a 20-year period, including whether they might be deemed austerity measures. The nature, relative weight, and frequency of measures, along with the evolution of public drug expenditure, were assessed. Results: Although there were fluctuations, frequency tended to increase. The highest number of policy changes per year was in 2010, a year before the financial assistance. The Troika intervention was characterized by a strong emphasis on pricing and prescription-related initiatives. Generic medicines played a significant role in the effort to reduce public drug expenditure. Conclusions: During the Troika intervention, outpatient public drug expenditure was consistently reduced through a comprehensive “package of measures” aimed at both the demand and supply sides. The effectiveness of some previous independent measures, if any, was temporary.

BACKGROUND/OBJECTIVE:The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at comparing the relative safety of the different JAK inhibitors with regard to the risk of serious infections in patients with rheumatoid arthritis. METHODS:PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with rheumatoid arthritis. The outcomes assessed were the risk of total and serious infections, tuberculosis, and herpes zoster. Sensitivity analysis disaggregated the results according to background therapy and licensed doses of JAK inhibitors. RESULTS:Thirty-seven randomized controlled trials that were included met the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95% confidence interval [CI], 1.39-16.66), etanercept (6.04; 95% CI, 1.79-20.37), peficitinib (7.56; 95% CI, 1.63-35.12), tofacitinib (4.29; 95% CI, 1.43-12.88), and upadacitinib (4.35; 95% CI, 1.46-13.00) have an increased risk of herpes zoster infection. Risk differences between the drugs became statistically nonsignificant when the sensitivity analysis was conducted. CONCLUSIONS:The risk of infections seems to be similar among the currently approved JAK inhibitor drugs. Although the initial results suggested that filgotinib could have a reduced risk of herpes zoster, the sensitivity analyses did not support those findings.