News

    

  ASCOT News                                                                                                                             1st November 2022         

     

Over several years we have entered into a collaboration with the HOMAGE Investigators as part of a European Union supported programme designed to investigate the role of cardiac fibrosis in heart failure and the identification of collagen biomarkers to monitor heart failure and the impact of treatment, particularly with mineralocorticoid antagonists such as spironolactone.


In ASCOT, data from patients with resistant hypertension at high risk of developing heart failure, and who were treated with spironolactone, were investigated for changes in serum concentrations of several collagen biomarkers following the initiation of spironolactone as add on therapy to other antihypertensive drugs.

 

In an appropriately controlled study, treatment with spironolactone was associated with a reduction in serum biomarkers of collagen synthesis independently of blood pressure, suggesting that spironolactone might exert favourable effects on myocardial collagen synthesis and fibrosis, providing a possible mechanism for a potential slowing of progression to heart failure with this class of drug.

 

We reported previously that in the UK we had been successful in our application to the Office of National Statistics and NHS Digital to obtain death certificates and electronic records of hospital admissions of participants in ASCOT from the UK, who had formerly participated in ASCOT-LLA and ASCOT-BPLA. By 2020/2021,  approximately 15 years after the end of the trial and 20 years following randomisation into the original trial, we had accumulated information from over 100,000 hospital admissions and 4000 deaths. We have almost completed the main analyses linking patient demographics at the time of randomisation, almost 1 million blood pressure measurements obtained during the trial and, subsequently, nearly 5000 cardiovascular events, 3000 coronary events, nearly 1000 strokes and over 2000 renal endpoints.

 

In the first paper to be published from these analyses, our collaborator, Dr Will Whitely from the University of Edinburgh, showed that visit-to-visit long-term systolic blood pressure variability was an important predictor of stroke and dementia and that participants, who had originally been randomised to amlodipine-based treatment, continued to show a long-term benefit on stroke compared with those originally assigned to beta blocker-based treatment.

 

We have continued with further analyses, the results of which, have been presented this year at the American Heart Association meeting on Hypertension in San Diego, the British and Irish Hypertension Society (BIHS) Meeting in York and the International Hypertension Society Meeting (ISH) in Kyoto, Japan.

 

In San Diego, Dr Somayeh Rostamian from our team at Imperial College, won the Paul Dudley White International Scholars Award for the best abstract submitted from the UK.  She had demonstrated that in the latest ASCOT analyses, involving over 2000 participants with one of several renal outcomes, including progression to chronic renal disease, renal failure or requirement for renal replacement therapy, long-term blood pressure variability was an important determinant of these renal endpoints, independent of mean systolic blood pressure.  In further analyses presented at the BIHS and ISH, we also demonstrated that blood pressure variability was a powerful determinant of long-term cardiovascular events, again independent of average systolic pressures. From these additional analyses, it was evident that high blood pressure variability, even in individuals with normal systolic pressure, conferred a very high risk of cardiovascular endpoints and substantially greater than the risk of higher levels of average blood pressure in those with low variability.  We also demonstrated that, as observed and reported in the original trial, treatment with an amlodipine-based strategy conferred substantial long-term benefits on cardiovascular outcomes, which we attribute to its effects on lowering blood pressure variability. Manuscripts relating to these presentations are currently being prepared for submission.

 

These remarkable observations on the importance of visit-to-visit variability, methods for its evaluation, the cardiovascular consequences and its treatment, raise serious questions for future recommendations and guidelines on blood pressure management.

 

Peter Sever

 

Note. Latest manuscripts added to the publication section

            ISH 2022 presentation added to Slides and Resources section

                                                                                                                                                                                        





 

ASCOT News                                                                                                                            15th December 2018


Another good year for ASCOT.  We have completed the 16-year follow-up programme for mortality outcomes. 

These were presented at the European Society of Cardiology Meeting in Munich in August, and simultaneously published in the Lancet, with an accompanying editorial. We confirmed the long term legacy of atorvastatin 

treatment on cardiovascular death, but reported, for the first time, observations that assignment to the 

amlodipine-based treatment in the original trial conferred a long term protection against stroke, compared with those originally assigned to the beta-blocker –based treatment regimen. These are remarkable findings and are challenging the authors to provide an explanation for these results.


We have just learned that NHS Digital in the UK, which holds all patient records, not only for mortality but for 

hospitalisation outcomes, will release data to us on ASCOT UK patients. This will enable us to pursue our objectives for investigating in trial predictors of all major cardiovascular outcomes including non-fatal and fatal events, and will incorporate our extensive biomarker and genetic resource.


We have also initiated an exciting collaboration with Dr Will Whitely, University of Edinburgh, in order to study 

predictors of dementia, based on our in trial observations on the impact of lipid-lowering and antihypertensive treatment on long term indicators of cognitive function impairment.


Finally, we are in the process of revising a manuscript for publication on the preferential use of non-fasting lipid values compared with those obtained from fasting blood samples on cardiovascular outcomes, using samples 

obtained at baseline in ASCOT.  Although guidelines now recommend the use of non-fasting samples, no single trial has allowed a comparison of both fasting and non-fasting samples on cardiovascular outcomes, and data from 

ASCOT on this important topic will shortly be published.



Peter Sever 



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                                                                                                                                                                   25th October 2017

 

ASCOT Update


Earlier this year the results of the analysis of adverse events in ASCOT-LLA were published in the Lancet (2017;389:2473-2481). The conclusion from the analyses was that the nocebo effect of the statin was the most likely explanation for the increase in reporting of adverse events in observational studies with statins when compared with blinded, randomised clinical trials, where there is no apparent excess of adverse event reporting.   These results were widely reported in the media where the opportunity was taken to stress the importance and safety of statins in the prevention of cardiovascular disease.

 

The long-term legacy of ASCOT continues to be a focus of research activity. The availability of hospital based records, in addition to mortality statistics, now means that we will be able to publish a much more comprehensive review of the long-term implications of lipid lowering and optimisation of blood pressure treatment in the patients originally recruited into the trial.

 

The ASCOT bio-resource continues to contribute to a number of meta-analyses of genetic determinants of cardiovascular and other diseases.

 

Updated publications appear in the bibliography section of this website.

 

 







Peter Sever

                                    



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                                            18th October 2016 


Newsletter Update 


Since the previous newsletter, further ASCOT presentations and publications have been forthcoming. The results of the comprehensive adverse event analyses from the lipid-lowering arm of the trial were presented at both the European Society of Cardiology meeting in Rome in August, and at the International Society of Hypertension meeting in Seoul in September. These analyses of ASCOT-LLA clearly showed that the reporting of adverse events, in particular muscle related symptoms, was restricted to the open phase of the lipid-lowering arm when patients were aware that they were taking atorvastatin. During the blinded phase of the trial, when atorvastatin was compared with placebo, there was no excess reporting of muscle related symptoms. These analyses, which are currently being submitted to a journal, confirm what is known as the nocebo effect of a drug - that is a treatment that appears to cause an adverse effect on a person, although it has no known biological mechanism.

 

Also in September, a meeting was called of the UK ASCOT investigators, to present the results of the 15-year long-term mortality and morbidity follow-up of ASCOT patients. These interesting results confirm the long-term legacy benefit of the statin in the lipid-lowering arm, particularly on all-cause mortality. These data will also be submitted for publication.

 

We have now uploaded onto the website six tables relating to the serious adverse events reported in the lipid-lowering arm of ASCOT, in addition to the adverse events which led to permanent discontinuation of drugs in the trial. These data had previously been submitted to the FDA, but have not been published. These analyses confirmed the safety of the statin and in the blinded phase of the trial, there was no excess of serious adverse events associated with atorvastatin compared with placebo. The reports of myalgia, leading to discontinuation of the drug occurred in 17 patients on atorvastatin and 9 patients on placebo – an access of approximately 1 in 1000 patients. Further data on adverse events will be uploaded following the publication of more recent analyses.

 

 



 



Peter Sever


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                                             1st  June 2016

ASCOT Update


A Century of Publications

 

The anniversary of the “century” of ASCOT publications has passed us by!  By the end of May this year at least 144 manuscripts had been published, including 24 pooled or meta-analyses, to which ASCOT data (mainly the genetic data resource) have contributed.  A list of all these papers has been updated on the publications section of the website. Many congratulations to all who have contributed to this remarkable achievement.

Upcoming highlights for 2016 include a presentation, in a Late Breaking Science Session at the ESC in September, of the final results of “MYASCOT”. In this study, involving a comprehensive evaluation of over 300,000 reported events, we have investigated the reports of muscle-related symptoms and other published (but unproven) adverse effects of statins, during blinded and un-blinded use  in the ASCOT-lipid-lowering arm (LLA). Watch this space!

In conjunction with our new reports of ASCOT adverse events, we are uploading onto the website, comprehensive tables of serious adverse events and withdrawals from treatment, during ASCOT-LLA.  This information was submitted to the regulatory authorities on completion of the trial but has not been formally published.

We have also completed the 15 year follow-up of ASCOT patients in the UK. Analyses of mortality and morbidity data are currently being finalised with a view to presentation at meetings later this year on the “ASCOT Legacy”.

The ASCOT Biomarker programme continues with a collaboration with Samia Mora of Harvard University on the use of non-fasting lipids as predictors of cardiovascular outcomes, and an exciting proposal in collaboration with Naveed Sattar, University of Glasgow, to identify new predictors of cardiovascular endpoints with the SOMALOGIC platform using DNA technology, which can quantitatively measure over 1300 proteins.



Peter Sever



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                                               1st July 2015

ASCOT Update


Since the completion of both the lipid-lowering (LLA) and blood pressure-lowering (BPLA) arms of the trial in 2003 and 2005 respectively, there have been more than 70 publications arising from additional analyses of the trial data base and from substudy outcomes.  10 years on from trial closure there is an extensive programme of ASCOT-related research.


Analyses have been completed on more than 13 analytes in the biomarker programme and, in addition to the published studies, a comprehensive analysis is shortly to be completed on coronary risk prediction in hypertensive patients incorporating a panel of new and established biomarkers.


The ASCOT genetic repository has contributed to an increasing number of GWAS – based studies, the most recent being a high profile study on genetic risk, coronary heart disease events and the clinical benefit of statin therapy (Lancet 2015;385:2264).


ASCOT-ON is a follow-up study in the UK of mortality and, in a subsample, morbidity outcomes from 2005 until 2015.  The hypotheses arising from our earlier reports are that preferential treatment during the trial confers a long term benefit or legacy effect. We have already demonstrated this for atorvastatin in a previous publication 6 years after completion of ASCOT-LLA (Europ. Heart J 2011;20:2525).


Side effects of statins are a current hot topic. There is a major discrepancy between the outcomes of double blind, placebo-controlled trials of statins, where the incidence of side effects appears similar in those assigned statin or placebo, and observational studies where adverse events in those receiving statins is reported to occur in up to 20% of patients.  There is, however, no proof that these associations are causal.  In ASCOT–LLA, patients were assigned statin or placebo in a double blind fashion for 3.3 years, when the trial was prematurely terminated due to overwhelming benefits in favour of atorvastatin.  Following this, patients were offered open label statin for the remainder of the blood pressure lowering arm of the trial.  During this 2.2 year period approximately two-thirds of those previously assigned either atorvastatin or placebo took atorvastatin.  ASCOT is therefore unique in that, within a single trial with standardised procedures for data collection, including information on side effects, we will have outcomes recorded during blinded and unblinded use of a statin.  This information, which includes reports on over 300,000 potential adverse events, is currently being evaluated and will report within the next year.


Several further studies, including the outcomes of those who developed new onset diabetes, the effects of statins on renal function, and further studies on blood pressure and cholesterol variability are in the pipeline. 






Peter Sever