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1.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315482, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33853351

RESUMO

OBJECTIVE: We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease. Approach and Results: Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16-1.25] per 10 mm Hg increase, P=1×10-24; diastolic BP OR, 1.27 [1.18-1.35], P=4×10-11; MAP OR, 1.26 [1.19-1.33], P=6×10-16; pulse pressure OR, 1.31 [1.24-1.39], P=9×10-23). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of Ors, 1.06 [1.0-1.12], P=0.04; MAP ratio of OR, 1.15 [1.06-1.26], P=8.6×10-4; diastolic BP ratio of OR, 1.21 [1.08-1.35], P=6.9×10-4). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17-1.35], P=3×10-10; MAP OR, 1.14 [1.06-1.23], P=2×10-4). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via ß-blocker (OR, 0.74 per 10 mm Hg decrease in SBP [95% CI, 0.65-0.84]; P=5×10-6), loop diuretic (OR, 0.66 [0.48-0.91], P=0.01), and thiazide diuretic (OR, 0.57 [0.41-0.79], P=6×10-4) associated variants were protective of PAD. CONCLUSIONS: Higher BP is likely to cause PAD. BP-lowering through ß blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.

2.
Hypertension ; 77(2): 376-382, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33390040

RESUMO

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; P=1×10-11; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; P=3×10-8; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; P=8×10-9) and ß-blockers (OR, 0.61 [95% CI, 0.46-0.81]; P=6×10-4) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or ß-blockade could reduce the risk of AF.

4.
Epidemiology ; 31(6): 852-859, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32841987

RESUMO

BACKGROUND: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink. METHODS: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over. RESULTS: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that ß-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, ß-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives. CONCLUSIONS: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.

7.
Int J Epidemiol ; 49(4): 1132-1140, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335937

RESUMO

BACKGROUND: Evidence concerning the potential repurposing of antihypertensives for Alzheimer's disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer's disease. METHODS: We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer's disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer's disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets. RESULTS: There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer's disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153). CONCLUSIONS: Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer's disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer's disease, they may not do so via systolic blood pressure.

8.
Wellcome Open Res ; 4: 113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448343

RESUMO

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

9.
Alzheimers Res Ther ; 10(1): 51, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29843807

RESUMO

BACKGROUND: Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016. METHODS: We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer's disease, receiving their first prescription for each drug class-namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest. RESULTS: The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, - 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, - 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister's Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials. CONCLUSIONS: Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively.


Assuntos
Demência/tratamento farmacológico , Prescrições de Medicamentos , Nootrópicos/uso terapêutico , Patentes como Assunto , Guias de Prática Clínica como Assunto , Inibidores da Colinesterase/uso terapêutico , Inglaterra , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/uso terapêutico , Fatores de Tempo
10.
Int J Epidemiol ; 46(6): 2078-2089, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040597

RESUMO

Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR addresses some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either before or after approval of the drug, and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized, and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.


Assuntos
Reposicionamento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Análise da Randomização Mendeliana , Farmacovigilância , Humanos , Prognóstico
11.
Int J Epidemiol ; 46(5): 1627-1632, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575313

RESUMO

Background: Instrumental variable analysis, for example with physicians' prescribing preferences as an instrument for medications issued in primary care, is an increasingly popular method in the field of pharmacoepidemiology. Existing power calculators for studies using instrumental variable analysis, such as Mendelian randomization power calculators, do not allow for the structure of research questions in this field. This is because the analysis in pharmacoepidemiology will typically have stronger instruments and detect larger causal effects than in other fields. Consequently, there is a need for dedicated power calculators for pharmacoepidemiological research. Methods and Results: The formula for calculating the power of a study using instrumental variable analysis in the context of pharmacoepidemiology is derived before being validated by a simulation study. The formula is applicable for studies using a single binary instrument to analyse the causal effect of a binary exposure on a continuous outcome. An online calculator, as well as packages in both R and Stata, are provided for the implementation of the formula by others. Conclusions: The statistical power of instrumental variable analysis in pharmacoepidemiological studies to detect a clinically meaningful treatment effect is an important consideration. Research questions in this field have distinct structures that must be accounted for when calculating power. The formula presented differs from existing instrumental variable power formulae due to its parametrization, which is designed specifically for ease of use by pharmacoepidemiologists.


Assuntos
Interpretação Estatística de Dados , Farmacoepidemiologia/métodos , Padrões de Prática Médica , Fatores de Confusão Epidemiológicos , Humanos
12.
BMJ Open ; 6(12): e012044, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27965247

RESUMO

INTRODUCTION: Current treatments for Alzheimer's and other neurodegenerative diseases have only limited effectiveness meaning that there is an urgent need for new medications that could influence disease incidence and progression. We will investigate the potential of a selection of commonly prescribed drugs, as a more efficient and cost-effective method of identifying new drugs for the prevention or treatment of Alzheimer's disease, non-Alzheimer's disease dementias, Parkinson's disease and amyotrophic lateral sclerosis. Our research will focus on drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all of which have previously been identified as potentially cerebroprotective and have variable levels of preclinical evidence that suggest they may have beneficial effects for various aspects of dementia pathology. METHODS AND ANALYSIS: We will conduct a hypothesis testing observational cohort study using data from the Clinical Practice Research Datalink (CPRD). Our analysis will consider four statistical methods, which have different approaches for modelling confounding. These are multivariable adjusted Cox regression; propensity matched regression; instrumental variable analysis and marginal structural models. We will also use an intention-to-treat analysis, whereby we will define all exposures based on the first prescription observed in the database so that the target parameter is comparable to that estimated by a randomised controlled trial. ETHICS AND DISSEMINATION: This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Demência/tratamento farmacológico , Reposicionamento de Medicamentos , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Esclerose Amiotrófica Lateral/prevenção & controle , Estudos de Coortes , Análise Custo-Benefício , Bases de Dados Factuais , Demência/prevenção & controle , Humanos , Análise Multivariada , Doença de Parkinson/prevenção & controle , Modelos de Riscos Proporcionais , Projetos de Pesquisa , Reino Unido
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