Publications
417 results found
Webster R, Salam A, De Silva HA, et al., 2018, Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 320, Pages: 566-579, ISSN: 0098-7484
Al-Lamee R, Howard JP, Shun-Shin MJ, et al., 2018, Fractional flow reserve and instantaneous wave-free ratio as predictors of the placebo-controlled response to percutaneous coronary intervention in stable single-vessel coronary artery disease: physiology-stratified analysis of ORBITA, Circulation, Vol: 138, Pages: 1780-1792, ISSN: 0009-7322
BACKGROUND : There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. METHODS : We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. RESULTS : Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and
Singh K, Crossan C, Laba T-L, et al., 2018, Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: Within-trial cost-effectiveness analysis of the UMPIRE trial, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 262, Pages: 71-78, ISSN: 0167-5273
BackgroundThe Use of Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial, showed that access to a cardiovascular polypill (aspirin, statin and two blood pressure lowering drugs) significantly improved adherence, lowered systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDLc) in patients with or at high risk of cardiovascular disease (CVD). We aimed to analyze the within-trial cost-effectiveness of the polypill strategy versus usual care in India.MethodsRelative effectiveness and costs of polypill versus usual care groups in UMPIRE were estimated from the health sector perspective. Only direct medical costs were considered. The effectiveness of the polypill was reported as a percentage increase in adherence and mean reductions in SBP, and LDL-c, over the 15-month trial period. Healthcare resource utilization and costs were collected for each patient during the trial. Polypill price was constructed using a range of scenarios: $0.06–$0.94/day. The cost-effectiveness of the polypill was measured as the additional cost for 10% increase in adherence, and per unit reduction in SBP and LDL-c.ResultsOverall, the mean cost per patient was significantly lower with the polypill strategy (−$203 per person, (95% CI: −286, −119, p < 0.01). In scenario analyses that varied polypill price assumptions, incremental cost-effectiveness ratios for a polypill strategy ranged between cost-saving to $75 per 10% increase in adherence for polypill price of $0.94 per day.ConclusionsThe polypill strategy was cost-saving compared to usual care among patients with or at high risk of CVD in India.
Williams B, MacDonald TM, Morant SV, et al., 2018, Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies, Lancet Diabetes and Endocrinology, Vol: 6, Pages: 464-475, ISSN: 2213-8595
BackgroundIn the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.MethodsPATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25–50 mg, bisoprolol 5–10 mg, and doxazosin 4–8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10–20 mg once daily on clinic systolic blood pressure during an optional 6–12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008–007149–30, and ClinicalTrials.gov, number NCT02369081.FindingsOf the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17–33]) of 126 patients were deemed to have inap
Crossan C, Dehbi H-M, Williams H, et al., 2018, A protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study., BMJ Open, Vol: 8, ISSN: 2044-6055
INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. METHODS AND ANALYSIS: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. DISSEMINATION: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies.
Al-Lamee R, Thompson D, Dehbi H-M, et al., 2018, Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial, Lancet, Vol: 391, Pages: 31-40, ISSN: 0140-6736
BACKGROUND: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding
McCarthy NS, Vangjeli C, Surendran P, et al., 2017, Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)., Atherosclerosis, Vol: 269, Pages: 42-49, ISSN: 0021-9150
BACKGROUND AND AIMS: Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. METHODS: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. RESULTS: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. CONCLUSIONS: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.
Sluyter JD, Hughes AD, Thom SAMG, et al., 2017, Arterial waveform parameters in a large, population-based sample of adults: relationships with ethnicity and lifestyle factors (vol 31, pg 305, 2017), JOURNAL OF HUMAN HYPERTENSION, Vol: 31, Pages: 760-760, ISSN: 0950-9240
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Sluyter JD, Camargo CA, Stewart AW, et al., 2017, Effect of Monthly, High-Dose, Long-Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy., Journal of the American Heart Association, Vol: 6, ISSN: 2047-9980
BACKGROUND: The effects of monthly, high-dose, long-term (≥1-year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. METHODS AND RESULTS: A total of 517 adults (58% male, aged 50-84 years) were recruited into a double-blinded, placebo-controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9-1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000-IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow-up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25-hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow-up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were -5.3 mm Hg (95% confidence interval [CI], -11.8 to 1.3) for brachial systolic BP (P=0.11), -2.8 mm Hg (95% CI, -6.2 to 0.7) for brachial diastolic BP (P=0.12), -7.5 mm Hg (95% CI, -14.4 to -0.6) for aortic systolic BP (P=0.03), -5.7 mm Hg (95% CI, -10.8 to -0.6) for augmentation index (P=0.03), -0.3 m/s (95% CI, -0.6 to -0.1) for pulse wave velocity (P=0.02), -8.6 mm Hg (95% CI, -15.4 to -1.9) for peak reservoir pressure (P=0.01), and -3.6 mm Hg (95% CI, -6.3 to -0.8) for backward pressure amplitude (P=0.01). CONCLUSIONS: Monthly, high-dose, 1-year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943.
Crossan CJ, Dehbi H, Thom S, et al., 2017, COST-EFFECTIVENESS OF A POLYPILL FOR PATIENTS WITH OR AT HIGH RISK OF CARDIOVASCULAR DISEASE IN AN NHS SETTING, Publisher: ELSEVIER SCIENCE INC, Pages: A620-A620, ISSN: 1098-3015
Crossan C, Dehbi H-M, Williams H, et al., 2017, Economic evaluation of a polypill for the treatment of patients with established or at high risk of cardiovascular disease (CVD): a UK-National Health Service study, Publisher: NATURE PUBLISHING GROUP, Pages: 664-664, ISSN: 0950-9240
Warren HR, Evangelou E, Cabrera CP, et al., 2017, Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk (vol 49, pg 403, 2017), NATURE GENETICS, Vol: 49, Pages: 1558-1558, ISSN: 1061-4036
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Webster R, Bullen C, Patel A, et al., 2017, Impact of switching to polypill based therapy by baseline potency of medication: post-hoc analysis of the SPACE Collaboration dataset, International Journal of Cardiology, Vol: 249, Pages: 443-447, ISSN: 0167-5273
BackgroundFixed dose combinations of cardiovascular therapy (‘polypills’) have now been launched in several dozen countries. There is considerable clinical interest in the effects of switching to polypill-based care from typical current treatment regimens, especially if polypills contain components at sub-maximal dosage.MethodsThe SPACE Collaboration includes three trials of polypill based care vs usual care in patients with established CVD or at high calculated risk. Individual patient data for 3140 trial participants were combined. Patients were categorized according to the potency of the statin and the number of BP lowering medications they were taking at baseline. Effects on adherence to anti-platelet medication, systolic blood pressure (SBP) and LDL cholesterol stratified by baseline potency of medication were determined using fixed effects models.ResultsRandomisation to the polypill group was associated with improved SBP at 12 months, but this improvement varied according to baseline BP regimen: − 3.3, − 5.9, − 2.5 and + 1 mm Hg for patients taking 0, 1, 2 and 3 + BP lowering medications at baseline. For changes in LDL cholesterol at 12 months, significant improvements in LDL cholesterol were seen for those taking no statin (− 0.21 mmol/L; 95% CI: − 0.34 to − 0.07), less potent statin (− 0.16 mmol/L; 95% CI: − 0.29 to − 0.04) and equipotent statins (− 0.14 mmol/L; 95% CI − 0.26 to − 0.02) at baseline.ConclusionThe adherence benefits of polypills tend to offset the loss of potency from use of individual components with lower dose potency, and to facilitate improvements in multiple risk factors.
Poulter NR, et al, 2017, Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney, Hypertension, Vol: 70, Pages: e4-e19, ISSN: 0194-911X
Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Bennett A, Chow CK, Chou M, et al., 2017, Efficacy and safety of quarter-dose blood pressure-lowering agents: A systematic review and meta-analysis of randomized controlled trials, Hypertension, Vol: 70, Pages: 85-93, ISSN: 0194-911X
There is a critical need for blood pressure–lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of −4.7/−2.4 mm Hg (P<0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a −6.7/ −4.4 mm Hg (P<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of −22.4/−13.1 mm Hg versus placebo (P<0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 (P<0.001), +1.3/−0.3 (NS), and −13.1/−7.9 (P<0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure–lowering therapy.
Segers P, O'Rourke MF, Parker K, et al., 2017, Towards a consensus on the understanding and analysis of the pulse waveform: Results from the 2016 Workshop on Arterial Hemodynamics: Past, present and future, ARTERY RESEARCH, Vol: 18, Pages: 75-80, ISSN: 1872-9312
Wild PS, Felix JF, Schillert A, et al., 2017, Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function, JOURNAL OF CLINICAL INVESTIGATION, Vol: 127, Pages: 1798-1812, ISSN: 0021-9738
BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
Riddell MA, Edwards N, Thompson SR, et al., 2017, Developing consensus measures for global programs: Lessons from the Global Alliance for Chronic Diseases Hypertension research program, Globalization and Health, Vol: 13, ISSN: 1744-8603
Background: The imperative to improve global health has prompted transnational research partnerships to investigate common health issues on a larger scale. The Global Alliance for Chronic Diseases (GACD) is an alliance of national research funding agencies. To enhance research funded by GACD members, this study aimed to standardise data collection methods across the 15 GACD hypertension research teams and evaluate the uptake of these standardised measurements. Furthermore we describe concerns and difficulties associated with the data harmonisation process highlighted and debated during annual meetings of the GACD funded investigators. With these concerns and issues in mind, a working group comprising representatives from the 15 studies iteratively identified and proposed a set of common measures for inclusion in each of the teams' data collection plans. One year later all teams were asked which consensus measures had been implemented. Results: Important issues were identified during the data harmonisation process relating to data ownership, sharing methodologies and ethical concerns. Measures were assessed across eight domains; demographic; dietary; clinical and anthropometric; medical history; hypertension knowledge; physical activity; behavioural (smoking and alcohol); and biochemical domains. Identifying validated measures relevant across a variety of settings presented some difficulties. The resulting GACD hypertension data dictionary comprises 67 consensus measures. Of the 14 responding teams, only two teams were including more than 50 consensus variables, five teams were including between 25 and 50 consensus variables and four teams were including between 6 and 24 consensus variables, one team did not provide details of the variables collected and two teams did not include any of the consensus variables as the project had already commenced or the measures were not relevant to their study. Conclusions: Deriving consensus measures across diverse research project
Lafeber M, Spiering W, Visseren FLJ, et al., 2017, Impact of switching from different treatment regimens to a fixed-dose combination pill (polypill) in patients with cardiovascular disease or similarly high risk: The influence of baseline medication on LDL-cholesterol, blood pressure and calculated risk reduction when switching to a cardiovascular polypill, EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, Vol: 24, Pages: 951-961, ISSN: 2047-4873
Chow CK, Thakkar J, Bennett A, et al., 2017, Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review, LANCET, Vol: 389, Pages: 1035-1042, ISSN: 0140-6736
Background:Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs.Methods:We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill—a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis.Findings:Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively.
Warren HR, Evangelou E, Cabrera CP, et al., 2017, Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk, Nature Genetics, Vol: 49, Pages: 403-415, ISSN: 1546-1718
Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.
Sluyter JD, Hughes AD, Thom SAMG, et al., 2016, Arterial waveform parameters in a large, population-based sample of adults: relationships with ethnicity and lifestyle factors, Journal of Human Hypertension, Vol: 31, Pages: 305-312, ISSN: 0950-9240
Little is known about how aortic waveform parameters vary with ethnicity and lifestyle factors. We investigated these issues in a large, population-based sample. We carried out a cross-sectional analysis of 4798 men and women, aged 50–84 years from Auckland, New Zealand. Participants were 3961 European, 321 Pacific, 266 Maori and 250 South Asian people. We assessed modifiable lifestyle factors via questionnaires, and measured body mass index (BMI) and brachial blood pressure (BP). Suprasystolic oscillometry was used to derive aortic pressure, from which several haemodynamic parameters were calculated. Heavy alcohol consumption and BMI were positively related to most waveform parameters. Current smokers had higher levels of aortic augmentation index than non-smokers (difference=3.7%, P<0.0001). Aortic waveform parameters, controlling for demographics, antihypertensives, diabetes and cardiovascular disease (CVD), were higher in non-Europeans than in Europeans. Further adjustment for brachial BP or lifestyle factors (particularly BMI) reduced many differences but several remained. Despite even further adjustment for mean arterial pressure, pulse rate, height and total:high-density lipoprotein cholesterol, compared with Europeans, South Asians had higher levels of all measured aortic waveform parameters (for example, for backward pressure amplitude: β=1.5 mm Hg; P<0.0001), whereas Pacific people had 9% higher loge (excess pressure integral) (P<0.0001). In conclusion, aortic waveform parameters varied with ethnicity in line with the greater prevalence of CVD among non-white populations. Generally, this was true even after accounting for brachial BP, suggesting that waveform parameters may have increased usefulness in capturing ethnic variations in cardiovascular risk. Heavy alcohol consumption, smoking and especially BMI may partially contribute to elevated levels of these parameters.
Sofat R, Cooper JA, Kumari M, et al., 2016, Circulating apolipoprotein E concentration and cardiovascular disease risk: meta-analysis of results from three studies, PLOS MEDICINE, Vol: 13, ISSN: 1549-1277
BackgroundThe association of APOE genotype with circulating apolipoprotein E (ApoE) concentration and cardiovascular disease (CVD) risk is well established. However, the relationship of circulating ApoE concentration and CVD has received little attention.Methods and FindingsTo address this, we measured circulating ApoE concentration in 9,587 individuals (with 1,413 CVD events) from three studies with incident CVD events: two population-based studies, the English Longitudinal Study of Ageing (ELSA) and the men-only Northwick Park Heart Study II (NPHSII), and a nested sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). We examined the association of circulating ApoE with cardiovascular risk factors in the two population-based studies (ELSA and NPHSII) and the relationship between ApoE concentration and coronary heart disease and stroke in all three studies. Analyses were carried out within study, and, where appropriate, pooled effect estimates were derived using meta-analysis. In the population-based samples, circulating ApoE was associated with systolic blood pressure (correlation coefficient 0.08, p < 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both p < 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both p < 0.001), high-density lipoprotein (correlation coefficient 0.16 and −0.14, respectively; both p < 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both p < 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, p = 0.001) and lipoprotein(a) (correlation coefficient −0.11, p < 0.001). In the pooled analysis of ASCOT, ELSA, and NPHSII, there was no association of ApoE with CVD events; the odds ratio (OR) for CVD events per 1-standard-deviation higher ApoE concentration was 1.02 (95% CI 0.96, 1.09).
Hughes AD, Falaschetti E, Witt N, et al., 2016, Association of Retinopathy and Retinal Microvascular Abnormalities With Stroke and Cerebrovascular Disease., Stroke, ISSN: 0039-2499
BACKGROUND AND PURPOSE: Abnormalities of the retinal circulation may be associated with cerebrovascular disease. We investigated associations between retinal microvascular abnormalities and (1) strokes and subclinical cerebral infarcts and (2) cerebral white matter lesions in a UK-based triethnic population-based cohort. METHODS: A total of 1185 participants (age, 68.8±6.1 years; 77% men) underwent retinal imaging and cerebral magnetic resonance imaging. Cerebral infarcts and white matter hyperintensities were identified on magnetic resonance imaging, retinopathy was graded, and retinal vessels were measured. RESULTS: Higher retinopathy grade (odds ratio [OR], 1.40 [95% confidence interval (95% CI), 1.16-1.70]), narrower arteriolar diameter (OR, 0.98 [95% CI, 0.97-0.99]), fewer symmetrical arteriolar bifurcations (OR, 0.84 [95% CI, 0.75-0.95]), higher arteriolar optimality deviation (OR, 1.16 [95% CI, 1.00-1.34]), and more tortuous venules (OR, 1.20 [95% CI, 1.09-1.32]) were associated with strokes/infarcts and white matter hyperintensities. Associations with quantitative retinal microvascular measures were independent of retinopathy. CONCLUSIONS: Abnormalities of the retinal microvasculature are independently associated with stroke, cerebral infarcts, and white matter lesions.
Thompson D, Hughes A, Kok HK, et al., 2016, Long-term anti-hypertensive treatment with amlodipine/perindopril results in lower carotid IMT than with atenolol/bendroflumethiazide in the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT), JOURNAL OF HUMAN HYPERTENSION, Vol: 30, Pages: 636-636, ISSN: 0950-9240
Thompson D, Hughes A, Mayet J, et al., 2016, Long-term treatment with atorvastatin does not improve diastolic function compared with placebo in hypertensive patients in the Anglo Scandinavian Cardiac Outcome Trial (ASCOT), JOURNAL OF HUMAN HYPERTENSION, Vol: 30, Pages: 646-646, ISSN: 0950-9240
Poulter N, Anjum A, Cross M, et al., 2016, LBOS 01-01A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR ABPM LEVELS: A RANDOMISED CROSS-OVER TRIAL (HARMONY)., Pages: e547-e547
OBJECTIVE: Some data suggest that nocturnal rather than daytime dosing of antihypertensive agents may have beneficial effects on consequent cardiovascular outcomes. This trial was designed to evaluate whether ABPM levels differ by timing of drug dosing, as a possible explanation for these observations. DESIGN AND METHOD: 103 male or female patients aged 18-80 years with "controlled" hypertension (≤150/≤90 mmHg) for at least three months on stable therapy of ≥1 antihypertensive agent were recruited from two centres; London and Thessaloniki. Patients were randomised to receive their usual therapy either in the morning or evening (6am-11am/6pm-11pm) for 12 weeks, then participants crossed-over to the alternative timing of drug administration for a further 12 weeks.Clinic BPs using standardised methodology and a 24 hour ABPM recording were taken at baseline, 12 and 24 weeks along with completion of the EQ-5D-5L quality of life questionnaire. The study was powered to detect 3mmHg difference in mean 24h SBP with 80% power and α = 0.05 significance level, and reached the target sample size. Regression model was used to calculate confidence intervals adjusted to centre, period (visit) and sequence (group). RESULTS: 95 patients (92%) completed all three ABPM recordings. The mean age of recruits was 52 years and 44% were female.24 hour systolic and diastolic BPs did not differ between daytime and nocturnal dosing (table). Similarly, there was no impact on mean daytime (7.00am-10.00pm) or night time (10pm-7.00am) ABPM levels, nor on clinic BP levels.Stratification by age (<65/≥65 years) and by gender did not affect the results. CONCLUSIONS: In patients with stable BP levels and hypertension diagnosed at least one year ago, the timing of antihypertensive drug administration (morning or evening) did not affect the mean 24 hour ABPM levels recorded.
Poulter NR, Anjum A, Cross M, et al., 2016, A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR AMBULATORY BLOOD PRESSURE MONITORING (ABPM) LEVELS: A RANDOMISED CROSS-OVER TRIAL, [OP.LB01.07] A COMPARISON OF THE IMPACT OF MORNING OR NIGHT DELIVERY OF ANTIHYPERTENSIVE AGENTS ON 24 HOUR AMBULATORY BLOOD PRESSURE MONITORING (ABPM) LEVELS: A RANDOMISED CROSS-OVER TRIAL, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E37-E38, ISSN: 0263-6352
Bunker J, Chang CL, Chapman N, et al., 2016, True Resistant Hypertension Following Observed Drug Ingestion: A Systematic Evaluation, Journal of Clinical Hypertension, Vol: 19, Pages: 250-255, ISSN: 1751-7176
The authors investigated the role of poor drug adherence in treatment-resistant hypertension following observed drug ingestion in 102 patients. Median blood pressures (BPs) were 170/91 mm Hg at referral, 153/84 mm Hg prior to, and 142/79 mm Hg during a 4- to 6-hour period after drug ingestion. Median daytime ambulatory BP monitoring (ABPM) over the following 24 hours was 142/80 mm Hg. Median BP at a final follow-up clinic visit was 147/79 mm Hg. The cumulative number of patients achieving a goal of <140/90 mm Hg in clinic or <135/85 mm Hg mean on ABPM was 57 (56%), with a further nine (9%) controlled at the final follow-up clinic visit. Thus, 65% of patients achieved a systolic BP <140 mm Hg at any point immediately prior to, or after, drug ingestion; the residual 35% were considered to have true resistant hypertension. In conclusion, among patients with suspected resistant hypertension, a minority were truly treatment-resistant following observed drug ingestion and BP monitoring.
Thompson DM, Mayet J, Hughes AD, et al., 2016, Long-term treatment with atorvastatin does not improve diastolic function compared with placebo in hypertensive patients in the Anglo Scandinavian cardiac outcome trial (ASCOT), Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 340-340, ISSN: 0195-668X
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