[Prescribing Trends of Benzodiazepine and other Sedatives in the Lisbon and Tagus Valley Regional Health Administration between 2013 and 2020: A Retrospective Study]. / Prescrição de Benzodiazepinas e outros Sedativos na Administração Regional de Saúde de Lisboa e Vale do Tejo de 2013 a 2020: Um Estudo Retrospetivo.

INTRODUCTION: Among the Organization for Economic Co-operation and Development members, Portugal has the highest reported consumption of anxiolytics, hypnotics, and sedatives, of which a large proportion are benzodiazepines or related drugs. These are known to cause tolerance and dependence. Other drugs with hypnotic effect, such as antidepressants, antihistamines, antipsychotics, or anticonvulsants have been identified by some reports as alternatives to benzodiazepines for the treatment of insomnia. In this regard, the aim of this study was to characterize the consumption of benzodiazepines, non-benzodiazepine anxiolytic, hypnotic or sedative effect drugs and other drugs with the potential to be used off-label to treat insomnia, and the results concerning benzodiazepine consumption related indicators in the primary health care setting in the Lisbon and Tagus Valley region. MATERIAL AND METHODS: From 2013 to 2020, a census, descriptive and retrospective study was conducted. The evolution of the variables total defined daily doses, defined daily doses per 1000 inhabitants per day (DHD) and relevant indicators were characterized. Data were extracted from the SIARS platform used in the Lisbon and Tagus Valley regional Health Administration. RESULTS: There was a decrease in the consumption of benzodiazepines (from 57.44 to 63.11 DHD) and an increase of non-benzodiazepines and of drugs with potential off-label use (from 6.56 to 8.56 DHD and from 14.70 to 25.95 DHD, respectively). Among non-benzodiazepines, zolpidem was the most consumed drug, also showing an increasing trend (from 4.86 to 6.96 DHD). For the group of drugs with off-label use potential, there was an increased consumption of trazodone (from 3.81 to 7.92 DHD), mirtazapine (from 3.52 to 6.48 DHD), pregabalin (from 3.15 to 4.87 DHD), quetiapine (from 2.68 to 4.59 DHD) and gabapentin (from 1.32 to 1.90 DHD), which was only the case (or, at least, more significantly) for the lower dose formulations. The median of results of the Primary Health Care setting indicator "proportion of elderly patients without prescription of sedatives, anxiolytics, and hypnotics", was 81.0 in 2015 and increased to 84.9 in 2020. For the indicator "proportion of patients without prolonged prescription of sedatives, anxiolytics, and hypnotics", the median was 93.6 in 2019 and 94.3 in 2020. CONCLUSION: There was, overall, a decreasing trend in the dispensing of benzodiazepines in the Lisbon and Tagus Valley Region. Even though this data suggests a change in the therapeutic pattern for insomnia, more robust studies are needed to confirm this observation.

Introdução: Portugal é o país da Organização para a Cooperação e Desenvolvimento Económico com maior consumo de ansiolíticos, hipnóticos e sedativos, sendo uma proporção significativa constituída por benzodiazepinas ou análogos, associados a efeitos de tolerância e dependência. Por este motivo, em alternativa às benzodiazepinas para tratamento da insónia, algumas publicações identificam outros fármacos com efeito hipnótico, como antidepressivos, anti-histamínicos, antipsicóticos ou anticonvulsivantes. Assim, torna-se necessário compreender a evolução do consumo destes medicamentos, pelo que foi objetivo deste estudo avaliar a evolução da dispensa de benzodiazepinas, outros fármacos ansiolíticos, hipnóticos ou sedativos não benzodiazepínicos, fármacos com potencial uso off-label na insónia e os resultados de indicadores dos Cuidados de Saúde Primários neste âmbito na região de Lisboa e Vale do Tejo. Material e Métodos: Realizou-se um estudo em base de dados, censitário e retrospetivo, no período de 2013 até 2020, avaliando-se a evolução das variáveis total de doses diárias definidas, doses diárias definidas por 1000 habitantes por dia (DHD) e dos indicadores relevantes. Os dados foram extraídos da plataforma SIARS da Administração Regional de Saúde de Lisboa e Vale do Tejo. Resultados: Verificou-se uma diminuição da dispensa de benzodiazepinas (de 57,44 para 51,77 DHD) mas o aumento da dispensa de não benzodiazepinas e de fármacos com potencial uso off-label (de 6,56 para 8,56 DHD e de 14,70 para 25,92 DHD, respetivamente). O zolpidem foi o mais dispensado entre os fármacos não benzodiazepínicos, acompanhando a tendência crescente de dispensa (de 4,86 para 6,96 DHD). Do conjunto de fármacos com potencial para uso off-label verificaram-se aumentos da dispensa para a trazodona (de 3,81 para 7,92 DHD), mirtazapina (de 3,52 para 6,48 DHD), pregabalina (de 3,15 para 4,87 DHD), quetiapina (de 2,68 para 4,59 DHD) e gabapentina (de 1,32 para 1,90 DHD), mas mais significativo ou apenas verificado nas formulações com dosagem mais baixa. A mediana dos resultados do indicador "proporção de idosos sem prescrição de sedativos, ansiolíticos e hipnóticos" em 2015 foi de 81,0, tendo em 2020 aumentado para 84,9. A mediana do indicador "proporção de utentes sem prescrição prolongada de ansiolíticos, sedativos e hipnóticos" em 2019 foi de 93,6 e aumentou para 94,3 em 2020. Conclusão: Globalmente, verificou-se uma redução da dispensa de benzodiazepinas prescritas na Região de Lisboa e Vale do Tejo. Parece existir uma alteração do padrão de prescrição no tratamento da insónia. São necessários estudos mais robustos para confirmar esta observação.

Atherosclerosis: The cost of illness in Portugal.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease is the leading cause of death in Portugal and atherosclerosis is the most common underlying pathophysiological process. The aim of this study was to quantify the economic impact of atherosclerosis in Portugal by estimating disease-related costs. METHODS: Costs were estimated based on a prevalence approach and following a societal perspective. Three national epidemiological sources were used to estimate the prevalence of the main clinical manifestations of atherosclerosis. The annual costs of atherosclerosis included both direct costs (resource consumption) and indirect costs (impact on population productivity). These costs were estimated for 2016, based on data from the Hospital Morbidity Database, the health care database (SIARS) of the Regional Health Administration of Lisbon and Tagus Valley including real-world data from primary care, the 2014 National Health Interview Survey, and expert opinion. RESULTS: The total cost of atherosclerosis in 2016 reached 1.9 billion euros (58% and 42% of which was direct and indirect costs, respectively). Most of the direct costs were associated with primary care (55%), followed by hospital outpatient care (27%) and hospitalizations (18%). Indirect costs were mainly driven by early exit from the labor force (91%). CONCLUSIONS: Atherosclerosis has a major economic impact, being responsible for health expenditure equivalent to 1% of Portuguese gross domestic product and 11% of current health expenditure in 2016.

Opioids prescribing trend between 2013 and 2017 in the Lisbon and Tagus Valley region, Portugal.

Background In the United States of America, the increased use of opioids is associated with serious risks, such as overdose, opioid use disorder and death. In Portugal, data about the use of these drugs are scarce. Objective Characterize the prescribing patterns of opioids in the Health Administrative Region of Lisbon and Tagus Valley. Methods Observational, retrospective descriptive analysis of the prescription of opioid drugs through the Health Administrative Region database from 2013 to 2017. The outcomes analysed were the defined daily dose (DDD) per year and the defined daily dose per 1000 inhabitants per year (DID). Results The prescription of opioid drugs in this region has increased approximately 1.5-fold over a 4 year period (totals of 4.32 million DDD and 3.25 DID in 2013 to totals of 7.21 million DDD and 5.42 DID in 2017). The opioids with the greatest absolute increase in this period were tramadol, tapentadol and codeine. Conclusion The prescription of opioid drugs has increased approximately 1.5-fold over a 4 year period in the ambulatory care of one of the main health administrative regions in Portugal. This trend warrants monitoring and suggests the need for highlighting good practices for opioids prescribing.

Radiofrequency catheter ablation of ventricular tachycardia in ischemic heart disease in light of current practice: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Ventricular tachycardia (VT) is a frequent cause of mortality and morbidity in patients with ischemic heart disease (IHD). We aim to perform a systematic review and meta-analysis of randomized controlled trials (RCT) of radiofrequency catheter ablation (RCA) of VT in patients with IHD and to discuss its appropriate timing and limitations. METHODS: Literature searches of MEDLINE, CENTRAL, the Cochrane Database of Systematic Reviews, Health Technology Assessment, and PsycINFO were performed in February 2020. RCTs comparing RCA vs conventional management for VT in patients with IHD and previous or planned implantable cardioverter defibrillator (ICD) were identified. Clinical outcomes included all-cause mortality, cardiovascular mortality, cardiovascular hospitalization, VT storm, recurrent VT/ventricular fibrillation (VF), appropriate ICD therapies, and appropriate ICD shocks. Using a random-effects model, relative risk (RR) and 95% confidence intervals (CI) were calculated for each outcome. RESULTS: A total of 6 RCTs (N = 791) met inclusion criteria. RCA was associated with significantly lower VT storm (RR 0.70; CI95% 0.51 to 0.94, p = 0.02) and appropriate ICD therapies (RR 0.69; CI95% 0.54 to 0.88, p = 0.003), including appropriate ICD shocks (RR 0.66; CI95% 0.47 to 0.92, p = 0.02). There was no significant difference in all-cause or cardiovascular mortality, cardiovascular hospitalization, and recurrent VT/VF. CONCLUSIONS: Radiofrequency catheter ablation for VT in patients with IHD was associated with a reduced risk of VT storm, ICD therapies, and ICD shocks. There is a need for future carefully designed RCTs that incorporate improved RCA procedural aspects.

Influenza vaccination in patients with heart failure: a systematic review and meta-analysis of observational studies.

OBJECTIVE: Despite the progression of treatments over decades, heart failure (HF) is a disease with high morbidity, mortality and economic burden. Influenza infection is an important trigger for cardiovascular (CV) events, including HF. Influenza vaccination has been seen to reduce the risk of CV mortality in patients with coronary disease, but the effect in patients with HF is still unclear. Therefore, we conducted a systematic review to evaluate the effect of influenza vaccination in the morbimortality of patients with HF. METHODS: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Technology Assessment and PsycINFO databases (December 2018) were searched for longitudinal studies evaluating influenza vaccination compared with a non-vaccination control group in patients with HF. The risk of bias was assessed according to the ROBINS-I tool. We performed a random-effects meta-analysis to estimate the pooled HRs with 95% CIs, and heterogeneity was evaluated using the I2 statistics. RESULTS: Six cohort studies evaluating 179 158 patients with HF were included in the meta-analysis. Influenza vaccination was associated with a lower risk of all-cause mortality (HR=0.83; 95% CI 0.76 to 0.91; I2=75%). The effect of the influenza vaccination was not statistically significant in a pooled analysis of CV mortality (HR=0.92, 95% CI 0.73 to 1.15; 2 studies) and of all-cause hospitalisations (HR=1.01, 95% CI 0.92 to 1.11; 2 studies). The majority of outcomes in the included studies had a serious risk of bias and almost all evaluated outcomes had very low Grading of Recommendation, Assessment, Development and Evaluation (GRADE) evidence. CONCLUSIONS: Influenza vaccination was associated with a significant decrease in all-cause mortality risk in patients with HF.

The current and future burden of heart failure in Portugal.

AIMS: Heart failure (HF) is a clinical syndrome with significant social and economic burden. We aimed to estimate the burden of HF in mainland Portugal over a 22-year time horizon, between 2014 and 2036. METHODS AND RESULTS: Heart failure burden was measured in disability-adjusted life years (DALYs), resulting from the sum of years of life lost (YLL) due to premature death and years lost due to disability (YLD). YLL were estimated based on the Portuguese mortality rates reported by the European Detailed Mortality Database. For YLD, disease duration and the overall incidence were estimated using an epidemiological model developed by the World Health Organization (DISMOD II). Disability weights were retrieved from published literature. The impact of ageing was estimated with a shift-share analysis using official demographic projections. In 2014, 4688 deaths were attributed to HF, corresponding to 4.7% of the total deaths in mainland Portugal. DALYs totalled 21 162, 53.9% due to premature death (YLL: 11 398) and 46.1% due to disability (YLD: 9765). Considering only population ageing over a 22-year horizon, the deaths and burden of HF are expected to increase by 73.0% and 27.9%, respectively, reaching 8112 deaths and 27 059 DALYs lost due to HF in 2036. DALY's growth is mainly driven by the increase of YLL, whose contribution to overall burden will increase to 62.0%. CONCLUSIONS: Heart failure is an emerging and growing health problem where significant health gains may be obtained. The projected significant increase of HF burden highlights the need to set HF as a priority for healthcare system.

Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for atrial fibrillation in Portugal.

INTRODUCTION AND OBJECTIVES: Recently, three novel non-vitamin K antagonist oral anticoagulants received approval for reimbursement in Portugal for patients with non-valvular atrial fibrillation (AF). It is therefore important to evaluate the relative cost-effectiveness of these new oral anticoagulants in Portuguese AF patients. METHODS: A Markov model was used to analyze disease progression over a lifetime horizon. Relative efficacy data for stroke (ischemic and hemorrhagic), bleeding (intracranial, other major bleeding and clinically relevant non-major bleeding), myocardial infarction and treatment discontinuation were obtained by pairwise indirect comparisons between apixaban, dabigatran and rivaroxaban using warfarin as a common comparator. Data on resource use were obtained from the database of diagnosis-related groups and an expert panel. Model outputs included life years gained, quality-adjusted life years (QALYs), direct healthcare costs and incremental cost-effectiveness ratios (ICERs). RESULTS: Apixaban provided the most life years gained and QALYs. The ICERs of apixaban compared to warfarin and dabigatran were €5529/QALY and €9163/QALY, respectively. Apixaban was dominant over rivaroxaban (greater health gains and lower costs). The results were robust over a wide range of inputs in sensitivity analyses. Apixaban had a 70% probability of being cost-effective (at a threshold of €20 000/QALY) compared to all the other therapeutic options. CONCLUSIONS: Apixaban is a cost-effective alternative to warfarin and dabigatran and is dominant over rivaroxaban in AF patients from the perspective of the Portuguese national healthcare system. These conclusions are based on indirect comparisons, but despite this limitation, the information is useful for healthcare decision-makers.

Tolerability and Acceptability of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Meta-Analysis.

BACKGROUND: The non-vitamin K antagonist oral anticoagulants (NOACs) overcame some limitations of vitamin K antagonists (VKAs), and are at least as effective in stroke prevention, with an additional decrease of intracranial bleeding risk. The transferability of these benefits to the real world requires tolerability (related to adverse events) and acceptability (drug discontinuation) profiles at least similar to VKAs. METHODS: We performed a systematic review with meta-analysis of randomized controlled trials (RCTs) evaluating NOACs versus VKAs in patients with non-valvular atrial fibrillation (AF). Studies were searched in April 2015 through MEDLINE, the Cochrane Collaboration's Database, Health Technology Assessment (HTA), Web of Science, and regulatory agencies' documents. Serious adverse events (SAEs) as well as drug-related and patient-related discontinuation rates were the outcomes of interest. Random-effects meta-analysis was performed, and the results expressed as risk ratios (RRs) and 95 % confidence intervals (CIs). Heterogeneity was evaluated with I (2) test. RESULTS: Five RCTs evaluating four NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) and 72,720 patients were included. Overall, NOACs were associated with a 4 % risk reduction of SAEs (95 % CI 2-6; I (2) = 0 %). Drug-related and patient-related discontinuation rates were similar between NOACs and VKAs (RR 1.03 [0.88-1.21] and RR 0.99 [0.89-1.10], respectively). Significant heterogeneity (I (2) ≥ 75 %) was found among studies results, which could be, at least partially, explained by the findings of the open-label dabigatran trial. CONCLUSIONS: NOACs were associated with a small, yet significant, risk reduction of SAEs in patients with AF. NOACs' drug-related and patient-related acceptability profiles were similar to those for VKAs. The results were heterogeneous mainly because of the increased rate of discontinuation associated with dabigatran. Pragmatic trials and cohort studies should be conducted to further address these important clinical questions.

Burden of disease and cost of illness of atrial fibrillation in Portugal.

INTRODUCTION AND OBJECTIVES: Atrial fibrillation is the most prevalent sustained arrhythmia. This paper estimates the burden and cost of illness attributable to atrial fibrillation in Portugal based on demographic and health statistics. METHODS: Mortality data by cause of death came from the European Detailed Mortality Database of the World Health Organization (WHO). Hospital data were taken from the Portuguese diagnosis-related groups database. The burden of disease was measured using DALYs (disability-adjusted life years), a metric adopted by the WHO. Costs studied included resource use and lost productivity. The burden and cost of illness are those attributable to atrial fibrillation and its main complication, ischemic stroke. RESULTS: In Portugal, 4070 deaths were attributable to atrial fibrillation in 2010, corresponding to 3.8% of all deaths. In total, the burden of disease attributable to atrial fibrillation was estimated at 23,084 DALYs: 10,521 resulting from premature deaths (1.7% of the total DALYs due to death in 2010 in Portugal), and 12,563 resulting from disability. The total estimated direct costs attributable to atrial fibrillation at 2013 prices were €115 million: €34 million for inpatient care and €81 million for outpatient care. Indirect costs resulting from lost production due to disability were estimated at €25 million. CONCLUSIONS: Atrial fibrillation has an important social impact in Portugal due to its associated mortality and morbidity, and was responsible in 2013 for a total cost of €140 million, about 0.08% of gross domestic product.

[What is the benefit of salt reduction on blood pressure? Assessment of the Cochrane Review: Effect of longer-term modest salt reduction on blood pressure. He FJ, Li J, Macgregor GA. Cochrane Database Syst Rev. 2013 Apr 30;4:CD004937]. / Qual é o impacto da redução da ingestão de sal na pressão arterial? Análise da revisão sistemática Cochrane "Effect of longer-term modest salt reduction on blood pressure". He FJ, Li J, Macgregor GA. Cochrane Database Syst Rev. 2013 Apr 30;4:CD004937.

UNLABELLED: In the present article we evaluate and comment the systematic review from Cochrane Collaboration "Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev. 2013 Apr 30;4:CD004937". CLINICAL QUESTION: What is the impact of long-term (= 4 weeks) modest salt (sodium chloride) reduction on arterial blood pressure? CONCLUSIONS: This systematic review concluded that a moderate reduction in salt intake (mean reduction -4.4 g per day) resulted in statistically significant decreases in blood pressure (BP) that may be helpful in normotensive (-2.42 mmHg systolic BP; -1.00 mmHg diastolic BP) and hypertensive patients (-5.39 mmHg systolic BP; -2.82 mmHg diastolic BP). There were slight increases in physiological plasma renin activity, aldosterone and norepinephrine, without significant changes in lipid profile.

No presente artigo avaliamos e comentamos a Revisão Sistemática da Cochrane "Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev. 2013 Apr 30;4:CD004937".Questão Clinica: Qual o impacto a longo prazo (≥ 4 semanas) da restrição moderada de ingestão de sal na pressão arterial.Conclusões: Esta revisão sistemática concluiu que a restrição moderada de ingestão de sal (redução média -4,4 g por dia) diminuide forma significativa a pressão arterial (PA) em indivíduos normotensos (-2,42 mmHg PA sistólica; -1,00 mmHg PA diastólica) ou com hipertensão arterial (-5,39 mmHg PA sistólica; -2,82 mmHg PA diastólica). Verificaram-se ligeiros aumentos da actividade da renina plasmática, aldosterona e norepinefrina. Contudo, não se identificaram alterações significativas do perfil lipídico.