Thomas Macdonald

University of Dundee · Medicines Monitoring Unit (MEMO), Medical Research institute

Background The Standard care vs. Celecoxib Outcome Trial (SCOT) found similar risk of cardiovascular events with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and the COX-2 selective drug celecoxib. Whilst pre-clinical work has suggested roles for vascular and renal dysfunction in NSAID cardiovascular toxicity, our understanding of the...

Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with...

Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital platforms with...

BACKGROUND UMOD (uromodulin) has been linked to hypertension through potential activation of Na ⁺ -K ⁺ -2Cl ⁻ cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2...

Background Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may in...

Background Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective To determine whether allopurinol improves major cardiovascular outcomes in patie...

Alongside the lack of homogeneity among international guidelines and consensus documents on primary hyperaldosteronism, the National UK guidelines on hypertension do not provide extensive recommendations regarding the diagnosis and management of this condition. Local guidelines vary from area to area, and this is reflected in the current clinical p...

Background: There is no real-world evidence regarding the association between beta-blocker use and mortality or cardiovascular outcomes in patients with obstructive sleep apnoea (OSA). We aimed to investigate the impact of beta-blocker use on all-cause mortality and cardiovascular diseases (CVDs) in patients with OSA. Methods: We conducted a targe...

Background: Genome-wide association studies identified the major A allele of SNP rs13333226 to be associated with increased BP and uromodulin excretion. Observational studies indicate those with rs13333226-AA genotype have greater BP lowering in response to loop diuretics. Methods: This genotype blinded multi-centre trial (NCT03354897) enrolled hyp...

Background and aim: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients. Methods: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical ca...

Objective To observe the effect of the xanthine oxidase inhibitors Allopurinol and Febuxostat on blood pressure in adults with chronic hyperuricemia. Design and method This was a sub-study of the Febuxostat versus Allopurinol Streamlined Trial (FAST). FAST was a randomised controlled trial comparing the cardiovascular safety of febuxostat and allo...

Aims: We aimed to evaluate the association between metabolic syndrome (MetS) and longterm all-cause mortality. Methods: The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III) and Joint Interim Stat...

UNSTRUCTURED Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital p...

Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. The...

Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we pr...

Background Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. Methods We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 pri...

Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients wi...

Background Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. Methods ALL-...

Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping b...

Oxidative stress participates in the development and exacerbation of cardiovascular diseases (CVD). The ability to promptly quantify an imbalance in an individual reductive-oxidative (RedOx) state could improve cardiovascular risk assessment and management. Derivatives-reactive oxygen metabolites (d-ROMs) are an emerging biomarker of oxidative stre...

Open in new tabDownload slide Cardiovascular disease and gout.

Background Decentralised clinical trials (DCTs) are clinical trials where all or most trial activities occur in or near participants’ homes instead of hospitals or research sites. While more convenient for participants, DCTs may offer limited opportunities to build trust with investigators and trial teams. This qualitative analysis explored DCT sta...

Objectives To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination. Design VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease...

Background Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exe...

Home blood pressure monitor (HBPM) ownership prevalence and the factors that influence it are unclear. This study aimed to investigate factors associated with HBPM ownership among participants in the Treatment in Morning versus Evening (TIME) hypertension study. This study is a sub-analysis of the TIME study, a randomised trial investigating the ef...

The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-st...

Background The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxi...

Aims To evaluate, using quantitative and qualitative approaches, published data on the design and conduct of decentralised clinical trials (DCTs). Methods We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, ProQuest Dissertations and Theses, ClinicalTrials.gov, OpenGrey and Google Scholar for publications reporting, discussing, or evaluating decentral...

Various home blood pressure monitors (HBPMs) are available to the public for purchase but only some are validated against standardised protocols. This study aimed to assess whether HBPMs owned by participants taking part in a clinical trial were validated models. The TIME study is a decentralised randomised trial investigating the effect of antihyp...

A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the years 2015 and 2016. A total of 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. The prevalence of hypertension, diabetes mellitus, dyslipidaemia, and CVD were similar in urban and rural areas (49...

Introduction Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For com...

Background Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exem...

This study investigates factors associated with active participation, and long-term commitment, to home blood pressure monitoring (HBPM) in the TIME study, a remote clinical trial assessing the effectiveness of morning vs. evening dosing of antihypertensive medications on cardiovascular outcomes in adults with hypertension. Participants reporting H...

Aims We profile the lack of specific regulation for direct‐to‐patient postal supply (DTP) of clinical trial medications (investigational medicinal products, IMPs) calling for increased efficiency of patient‐centred multi‐country remote clinical trials. Methods Questionnaires emailed to 28 European Economic Area (EEA) Medical Product Licensing Auth...

Background: The purpose of the study was to evaluate secondary stroke prevention in Poland and its association with sociodemographic factors, place of residence, and concomitant cardiovascular risk factors. Material and methods: From all patients in LIPIDOGRAM2015 Study (n = 13,724), 268 subjects had a history of ischaemic stroke and were includ...

Background Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exem...

Aims The aim of the study was to identify actionable learning points from stakeholders in remote decentralised clinical trials (RDCTs) to inform their future design and conduct. Methods Semistructured interviews were carried out with a purposive sample of stakeholders, including senior managers, trial managers, technology experts, principal invest...

Introduction Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as “neo-antigens” and start production of autoantibodies. This study was designed to evaluate the relatio...

Objectives: Diagnosis of Systemic Autoimmune Rheumatic Diseases using antinuclear autoantibodies (ANA) is dependent on many factors and varies between populations, such that the screening dilution used for indirect immunofluorescence assay (IIFA) should be defined locally for each population. The aim of the study was firstly, to assess the prevalen...

Background Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. Objectives To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. Design A series of...

Objective To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. Design Series of randomised, placebo controlled n-of-1 trials. Setting Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. Participants 200 participants who had recently stopped o...

IntroductionA multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarc...

Abstract Objective Effervescent, soluble, dispersible formulations contain considerable amounts of sodium. In 2013, we previously confirmed the association between sodium-containing medications and cardiovascular risks. This study aimed to determine the changes in the prescribing pattern in clinical practice following this publication. Design A lo...

Background To manage the risk factors and to improve clinical outcomes, patients with stroke commonly receive multiple cardiovascular medications. However, there is a lack of evidence on the optimum combination of medication therapy in the primary care setting after ischemic stroke. Therefore, this study aimed to investigate the effect of multiple...

Background and aim: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients. Methods: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical...

Background Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro‐arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. M...

Introduction Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For com...

Abstract For most chronic medical conditions, multiple medications are available and prescribers often have limited evidence about which therapy is likely to be the most effective and safe for an individual patient. As many patients are exposed every day to medicines that may be less effective than available alternatives, this is of public health i...

Background Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. Methods We did a prospective, randomised...

Background There is evidence from genome wide association study that single-nucleotide polymorphisms (SNPs) in the 5' end of the uromodulin gene (UMOD) affect uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb of the loop of Henle (TAL) and its effect on BP appear to be mediated via...

Objective Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method Quarterly interrupted time series regression (ITS) analyses of diclofenac initiati...

This chapter reflects on one of the biggest product withdrawals in pharmaceutical history, known as the “Vioxx story”, and explores the discovery of cardiovascular risks with rofecoxib, the active substance in Vioxx®, and other COX-2 inhibitors, and the way that these risks were communicated to patients and healthcare professionals. It discusses sp...

Introduction: Cardiovascular disease (CVD) is a major cause of morbidity and mortality throughout the world. The LIPIDOGRAM2015 study was performed to estimate the prevalence of risk factors for atherosclerotic diseases as well as cardiovascular and related disorders in the primary care setting in Poland. The LIPIDOGEN2015 sub-study was designed to...

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescri...

Objectives: Previous studies have demonstrated that high-dose allopurinol is able to regress left ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high-dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well-controlle...

Introduction The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. Methods This observational population-...

Introduction Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. Objectives Our objective is to describe the methods and resulting comparability of...

Objective To investigate the incidence of new onset type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors (dutasteride or finasteride) for long term treatment of benign prostatic hyperplasia. Design Population based cohort study. Setting UK Clinical Practice Research Datalink (CPRD; 2003-14) and Taiwanese National Health Insur...

Background Recruitment to clinical trials can be challenging. Methods that improve the efficiency of trial recruitment are needed to increase successful study completions. The aim of this study was to ascertain whether sending an audio-visual presentation on a digital versatile disc (DVD), along with usual study invitation materials, would improve...

Background The Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity stage classifies Chronic Obstructive Pulmonary Disease (COPD) into groups based on symptoms, exacerbations and forced expiratory volume in one second (FEV1). This allows patients to change to less severe COPD stages, a novel aspect of assessment not previously eva...

The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relev...