Clinical pharmacology of oral anticoagulants : pharmacoepidemiology, safety and pharmacoeconomics

Tese de doutoramento, Medicina (Farmacologia Clínica), Universidade de Lisboa, Faculdade de Medicina, 2017INTRODUCTION Oral anticoagulant drugs are essential in the treatment and prevention of thromboembolic events in certain prothrombotic conditions. Atrial fibrillation is the most prevalent arrhythmia, and is the main indication for chronic oral anticoagulation due to its thrombotic complications. Vitamin K antagonists (VKA) were until recently the only therapeutic options of this class in Portugal, namely in the form of warfarin and acenocoumarol. Despite proven efficacy, VKAs have a large pharmacodynamic variability owing to multiple potential interactions with food and other drugs. The development of the non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) increased the therapeutic armamentarium for anticoagulation. NOACs act directly by blocking thrombin or factor Xa, and exhibit an antithrombotic effect at least as effective as VKAs. Since the myriad of interactions found with VKAs are absent in NOACs, the anticoagulant effect is predictable, and does not require serial evaluations of hemostasis, making NOACs more convenient for patients and clinicians. Thus, it is reasonable to expect that NOACs may be prescribed often than VKAs. However, the approval of NOACs was based on phase III randomized controlled trials (RCTs), which are seldom planned to evaluate the safety of interventions. Additionally, NOACs are costlier than VKAs, raising the question of whether these new anticoagulants promote health gains at a sustainable cost to the Portuguese society. Therefore, it is important to better characterize the oral anticoagulants with a focus on NOACs in the population-level clinical pharmacology, namely pharmacoepidemiology, safety aspects of the oral anticoagulants (comparative safety and pharmacovigilance) and pharmacoeconomics. OBJECTIVES The aim of this dissertation was to improve the knowledge related to the oral anticoagulants in the four main fields population-level clinical pharmacology: pharmacoepidemiology, comparative effectiveness/safety, pharmacovigilance, and pharmacoeconomics. Specific objectives: 1) Pharmacoepidemiology: To assess the state of oral anticoagulation in Portugal, in terms of proportion of non-anticoagulated patients, the quality of anticoagulation, and evolution of the prescription pattern since the licensing of NOACs. 2) Comparative effectiveness/safety research: To evaluate the safety of NOACs, based on clinical trials’ data, in terms of bleeding and non-bleeding adverse events, as well as the overall tolerability and acceptability of the drugs. 3) Pharmacovigilance: To identify adverse events related to oral anticoagulants most frequently reported to Pharmacovigilance Units in Portugal. 4) Pharmacoeconomics: To assess the cost and burden of AF in Portugal, and the relative cost-effectiveness of oral anticoagulants in Portugal. METHODS To achieve the objectives, the following research projects were conducted: 1) Pharmacoepidemiology: A systematic review and meta-analysis of all published studies in Portugal assessing the prescription/use of oral anticoagulant therapy in patients with AF; A retrospective observational study of a cohort of patients treated with VKAs for assessment of anticoagulation control quality through the Rosendaal Time in Therapeutic Range (TTR); A retrospective observational study of national outpatient prescribing oral anticoagulants, with characterization of the number of boxes sold and Defined Daily Dose (DDD, a standardized measure of the World Health Organization) prescribed for each group of drugs. 2) Comparative effectiveness/safety research: Systematic review and meta-analyses based on aggregated data of phase III RCTs of NOACs compared to VKAs, for bleeding events, overall tolerability, and acceptability; and NOACs compared to all available comparators for non-bleeding adverse events. The data were pooled using a randomeffects model, and expressed as relative risk (RR) with a confidence interval of 95% (95%CI). 3) Pharmacovigilance: A retrospective observational study of spontaneous reports related to oral anticoagulants, received by the National Pharmacovigilance System in Portugal. 4) Pharmacoeconomics: A study concerning the cost of illness and burden of AF, and a cost-effectiveness study of oral anticoagulants in Portugal for AF were performed. To the burden of disease assessment, disability-adjusted life years (DALYs) related to the AF were estimated, as well as both the direct (inpatient and outpatient) and indirect (lost productivity) associated costs. To evaluate the cost-effectiveness, a Markov model was used, with characteristics adjusted to Portugal. The relative costs and health gains associated with NOACs were estimated and weighed through the Incremental Cost Effectiveness Ratio (ICER), which evaluates the cost of each Quality-Adjusted Life Years (QALY) gained for a given intervention in relation to the control intervention (VKAs and all NOACs). RESULTS 1) About 60% of patients with AF in Portugal were not treated with oral anticoagulants, and oral anticoagulation with VKAs had a suboptimal control with a mean TTR of 61%, according with the single-centre retrospective study. Since the introduction of NOACs in the Portuguese market, the number of pack and DDD of oral anticoagulants prescribed increased significantly, this rise being due to NOACs. Currently the NOACs as pharmacological group have most of the market share of oral anticoagulants. 2) In the pooled safety data from phase III RCTs, NOACs were associated with a decreased risk of major bleeding (RR 0.72; 95% CI: 0.61 to 0.84; 12 RCTs), fatal bleeding (RR 0.52; 95% CI: 0.65 to 0.41; 12 RCTs) and ICH (RR 0.43; 95% CI: 12.36 to 12.51; 11 RCTs) compared to the VKA. Regarding major gastrointestinal, intraocular, and pericardial bleeding, there was no increase in the risk of these events. The NOACs are not associated with liver injury (RR 0.93; 95% CI: 0.75 to 1.15; 26 RCTs) or severe renal impairment (RR 0.93; 95% CI: 0.82 to 1.05; 7 RCTs). Similarly, there was no increased risk of infections or insomnia. The overall risk of serious adverse events was significantly decreased by NOACs compared to VKAs (RR 0.96; 95% CI: 0.94 to 0.98; 5 RCTs). The results for acceptability (drug discontinuation) were heterogeneous. However, for most NOACs the risk of treatment discontinuation due to drug-related or patient-related reasons were not increased compared to the VKAs in AF patients. 3) The Pharmacovigilance study data showed that most the reported adverse events were related to NOACs (78%). About 25% of these events were related to bleeding and 10% related thromboembolic events. The annual number of notifications has been increasing, but when adjusted to the degree of drugs exposure, the peak incidence was in 2012, with a subsequent decrease. 4) AF has an important burden in Portugal contributing to the yearly loss of 23084 DALYs and expenses of 141 million € (57% in direct costs and 43% in indirect costs). NOACs were shown to be cost-effective compared with VKAs for the prevention of thromboembolic events in non-valvular atrial fibrillation. In the presented model, apixaban was shown to be cost-effective compared to warfarin (ICER €5529/ QALY) and dabigatran (ICER €9163/QALY), and dominant compared to rivaroxaban. CONCLUSIONS The proportion of patients receiving oral anticoagulant treatment is increasing in Portugal, mostly due to NOACs. These drugs have an acceptable safety profile, with an improvement of the risk of fatal and serious bleeding events, particularly intracranial hemorrhage, without substantial increase in other non-bleeding events, including hepatic, renal, or infectious. The risk of adverse events is generally lower, and most NOACs do not show an increased risk of discontinuation. Although most adverse events reported to the National Pharmacovigilance system are associated with the NOACs, the number of events since the increase in drug exposure has declined. Atrial fibrillation, the main indication for oral anticoagulation, has an important burden, with costs related to the disease that account for about 0.1% of gross domestic product of Portugal. The NOACs use for stroke prevention in AF is cost-effective compared with VKAs

Myocardial infarction and viral triggers: what do we know by now?

© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Myocardial infarction (MI) is an acute clinical manifestation ischaemic heart disease, which is the leading cause of death worldwide. Infections also have an important burden worldwide, with lower respiratory infections being the worldwide leading cause of death due to communicable diseases. The relationship of MI with viral respiratory infections (including influenza and SARS-CoV-2) as a trigger has been well documented with significant associations. These infections can lead to Type 1 MI, where inflammation and vascular dysfunction, as well as the increased prothrombotic environment lead to atherothrombosis. Type 2 MI may also occur due to an imbalance of oxygen/blood supply and myocardial demand (hypoxaemia, fever, and tachycardia). The data from randomized controlled trials showing a potential benefit of influenza vaccination in coronary artery disease patients should not be ignored. This can be considered a further argument for the association of viral infections (influenza in particular) and MI.info:eu-repo/semantics/publishedVersio

Rate versus rhythm control in atrial fibrillation and clinical outcomes: Updated systematic review and meta-analysis of randomized controlled trials

SummaryAtrial fibrillation is the most frequently occurring sustained cardiac arrhythmia and is associated with a significantly increased risk of thromboembolic events and death. We sought to compare the clinical efficacy of rate and rhythm control strategies in patients with non-postoperative atrial fibrillation. We searched the PubMed database and the Cochrane Central Register of Controlled Trials for randomized controlled trials comparing rate versus rhythm control in patients with atrial fibrillation. Studies were retrieved and we analysed major clinical outcomes. Risk ratios (RRs) and 95% confidence intervals were calculated assuming random effects due to the clinical heterogeneity of the study populations. Eight randomized controlled trials were identified, with a total of 7499 patients with atrial fibrillation. There were no significant differences in the effects of rate and rhythm control on any outcome: all-cause mortality (RR: 0.95; CI: 0.86–1.05), cardiovascular mortality (RR: 0.99; CI: 0.87–1.13), arrhythmic/sudden death (RR: 1.12; CI: 0.91–1.38), ischaemic stroke (RR: 0.89; CI: 0.52–1.53), systemic embolism (RR: 0.89; CI: 0.69–1.14) and major bleeding (RR: 1.10; CI: 0.89–1.36). Updated data pooled from a large population of patients with atrial fibrillation suggests that rate and rhythm control strategies have similar effects on major clinical outcomes. Other factors, including individual preferences, comorbidities, drug tolerance and cost issues, should be considered when choosing the approach for these patients

Doentes cardiovasculares também beneficiam da vacina contra influenza

Copyright © Ordem dos Médicos 2020The COVID-19 pandemic has challenged all health care systems worldwide. Nevertheless, it is important to stress that there are other burdensome diseases such as influenza that should also be prevented and managed. Furthermore, the coinfection of COVID-19 and influenza is a matter of concern among healthcare professionals and the general population.info:eu-repo/semantics/publishedVersio

Influenza vaccination and prevention of cardiovascular disease mortality

© 2018 Elsevier Ltd. All rights reserved.In Europe, which has an influenza vaccination coverage of 45·6%, about 30 million individuals have ischaemic heart disease, and more than half a million of these people will die from cardiovascular causes (figures based on the conservative standardised mortality rates of individuals aged 65 years and older). Considering that influenza vaccination is associated with a 24% risk reduction of cardiovascular mortality in this population (the lower limit of 95% CI of the estimate), an increase of coverage to 75% (as recommended by the European Council) would translate to about 42 000 potentially avoidable cardiovascular deaths in Europe among individuals with ischaemic heart disease.info:eu-repo/semantics/publishedVersio

Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers : systematic review and meta-analysis

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/bync/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.OBJECTIVE: To systematically review longitudinal studies evaluating use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and risk of pneumonia. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline through PubMed, Web of Science with conference proceedings (inception to June 2011), and US Food and Drug Administration website (June 2011). Systematic reviews and references of retrieved articles were also searched. STUDY SELECTION: Two reviewers independently selected randomised controlled trials and cohort and case-control studies evaluating the use of ACE inhibitors or ARBs and risk of pneumonia and retrieved characteristics of the studies and data estimates. DATA SYNTHESIS: The primary outcome was incidence of pneumonia and the secondary outcome was pneumonia related mortality. Subgroup analyses were carried according to baseline morbidities (stroke, heart failure, and chronic kidney disease) and patients' characteristics (Asian and non-Asian). Pooled estimates of odds ratios and 95% confidence intervals were derived by random effects meta-analysis. Adjusted frequentist indirect comparisons between ACE inhibitors and ARBs were estimated and combined with direct evidence whenever available. Heterogeneity was assessed using the I(2) test. RESULTS: 37 eligible studies were included. ACE inhibitors were associated with a significantly reduced risk of pneumonia compared with control treatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I(2) = 79%) and ARBs (combined direct and indirect odds ratio estimate 0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia was also lower in those treated with ACE inhibitors compared with control treatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80). ACE inhibitors were associated with a significantly reduced risk of pneumonia among Asian patients (0.43, 0.34 to 0.54) compared with non-Asian patients (0.82, 0.67 to 1.00; P<0.001). Compared with control treatments, both ACE inhibitors (seven studies: odds ratio 0.73, 0.58 to 0.92; I(2)=51%) and ARBs (one randomised controlled trial: 0.63, 0.40 to 1.00) were associated with a decrease in pneumonia related mortality, without differences between interventions. CONCLUSIONS: The best evidence available points towards a putative protective role of ACE inhibitors but not ARBs in risk of pneumonia. Patient populations that may benefit most are those with previous stroke and Asian patients. ACE inhibitors were also associated with a decrease in pneumonia related mortality, but the data lacked strength.info:eu-repo/semantics/publishedVersio

Hypothermia-induced electrocardiographic changes

This is an open-access article distributed under the terms of the Creative Commons Attribution License.An elderly female patient was brought to the Emergency Department due to loss of consciousness. The past medical history was remarkable for hypercholesterolemia and essential hypertension. The patient was not treated with any negative chronotropic drug. At the admission, the patient’s blood pressure was 90/60 mmHg, she had bradycardia (42/minute), and hypothermia (33ºC). Electrocardiogram (ECG) showed sinus bradycardia, 1st grade atrioventricular block, long corrected QT interval, and Osborn waves at the end of QRS complexes ( Figure 1 A , arrowheads). Accordingly, these positive notching deflections were best seen in lateral precordial leads and disappeared after warming the patient to 36ºC ( Figure 1B ). The bradycardia, atrioventricular block, and QT prolongation were also resolved ( Figure 1 B ). During the inward stay, head computed tomography scan, 24-hour Holter, and laboratory analysis were unremarkable for pathological findings. Transthoracic echocardiogram only revealed degenerative aortic and mitral valve changes. This case is illustrative of hypothermia-induced electrocardiographic changes, namely prolongation of the PR, RR and QT intervals and particularly the presence of Osborn Waves.1info:eu-repo/semantics/publishedVersio

Aspirin in diabetic patients at primary prevention: insights of the VITAL cohort

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose: Aspirin use among patients with diabetes in primary prevention is still a matter of debate. We aimed to evaluate the potential cardiovascular risk benefit of aspirin in primary prevention, using data from a contemporary cohort. Methods: Retrospective analysis of the VITAL cohort with > 20,000 individuals at primary prevention who were followed for a median of 5.3 years. The population was evaluated according to the baseline diabetes status, and then aspirin use was evaluated among diabetic patients. Cox regression models were used to estimate the risks of mortality and cardiovascular outcomes. The estimates were reported using adjusted hazard ratio (HR) and 95% confidence intervals (95%CI). Results: Diabetic patients (n = 3549; 13.7%) showed to increase the risk of all-cause mortality (HR 1.61, 95%CI 1.33-1.94), and major adverse cardiovascular events (MACE) (HR 1.36 95%CI 1.11-1.68) than non-diabetic population. Diabetic patients taking aspirin were older, more frequently man, hypertensive, current users of statins, and current smokers compared with diabetic patients who did not use aspirin at baseline. There was no difference between diabetic aspirin users and non-users regarding all-cause mortality (HR 0.80, 95%CI 0.59, 1.10), MACE (HR 0.92, 95%CI 0.64, 1.33), coronary heart disease (HR 0.98, 95%CI 0.67, 1.43), or stroke (HR 0.87, 95%CI 0.48, 1.58). Conclusions: The VITAL data confirmed diabetes as an important risk factor for cardiovascular events in a contemporary cohort but did not show cardiovascular benefits of aspirin in primary prevention among people with diabetes who were shown to be at higher risk of cardiovascular events.Open access funding provided by FCT|FCCN (b-on)info:eu-repo/semantics/publishedVersio