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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