UOA02-03: Statin Therapy for Preventing Heart Attacks and Strokes
Submitting InstitutionUniversity of Oxford
Unit of AssessmentPublic Health, Health Services and Primary Care
Summary Impact TypePolitical
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services
Summary of the impact
Studies coordinated by the University of Oxford's Clinical Trial Service
Unit (CTSU) within the Nuffield Department of Population Health (NDPH)
have strongly influenced the labelling of statin medication
internationally, treatment guidelines, and the resulting changes in
prescribing have contributed to reductions in mortality and morbidity from
heart attack and ischaemic stroke in many countries. CTSU's randomised
trials and meta-analyses of trials have shown that lowering low-density
lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks,
strokes and revascularisation procedures in a wide range of people, and
work conducted in collaboration with the NDPH's Health Economic Research
Centre has provided clear evidence of cost-effectiveness of statins.
CTSU's Heart Protection Study (HPS), which commenced in 1994 and included
over 20,000 patients, showed that simvastatin 40mg daily reduced the risk
of heart attacks, strokes, and the need for arterial revascularisation
procedures in a wide range of people at high risk of cardiovascular
disease . At about the same time that the HPS began, CTSU set up a
collaborative meta-analysis called the Cholesterol Treatment Trialists'
(CTT) Collaboration, with the aim of providing more reliable information
about the effects of lowering LDL cholesterol on vascular and non-vascular
outcomes. The first CTT report in 2005 included data from around 90,000
patients in 14 randomised trials, and provided comprehensive information
that has helped to guide the use of statin therapy internationally . It
showed that treatment with a statin reduces the risk of heart attacks,
strokes and coronary revascularisation procedures, as well as the overall
risk of death, in a wide range of patients at risk of cardiovascular
disease. It also refuted previous concerns that statin therapy might
increase the risk of cancer, and non-cardiovascular causes of death .
In 2010, CTSU published the results of its Study of the Effectiveness of
Additional Reductions in Cholesterol and Homocysteine [SEARCH] trial 
comparing 80 mg versus 20 mg simvastatin daily among 12,000 heart attack
survivors. It showed that simvastatin 80mg produced further reductions in
major vascular events, but that the risk of myopathy was increased. In
tandem with this publication, the CTT published a meta-analysis of the
five major trials of intensive versus standard statin regimens (including
SEARCH), showing that more intensive regimens yield additional benefits,
and that this could be achieved safely with regimens other than
simvastatin 80mg. 
Recently, there has been controversy over whether statins are effective
for the prevention of first heart attacks and strokes in apparently
healthy people. In 2012, however, the CTT published a meta-analysis
showing definitively that the benefits of statin therapy clearly outweigh
the hazards in people at low risk of cardiovascular disease .
In addition to its work on the CTT collaboration, CTSU has also provided
the first reliable evidence that lowering cholesterol reduces the risk of
heart attacks and strokes among kidney patients. Its Study of Heart and
Renal Protection (SHARP) was the largest study of its kind, and included
over 9000 kidney patients in 380 hospitals from 18 countries. This study
showed that lowering cholesterol with the combination of a statin and a
drug that blocks cholesterol absorption, ezetimibe can reduce heart
attacks and strokes safely by about one quarter in kidney patients .
References to the research
. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high-risk
individuals: a randomised placebo-controlled trial. Lancet 360,
7-22 (2002). PubMed ID: 12114036. Primary paper from the Heart
Protection Study, showing that simvastatin 40mg daily reduced
the overall risk of death in a wide range of people at high
risk of cardiovascular disease.
. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and
safety of cholesterol-lowering treatment: prospective meta-analysis of
data from 90,056 participants in 14 randomised trials of statins. Lancet
366, 1267-1278 (2005). PubMed ID: 1621459. The first CTT
study indicating that statins reduce the risk of heart attacks,
strokes and coronary revascularisation. This study also showed
that statin therapy does not increase the risk of cancer or
non-cardiovascular causes of death.
. Study of the Effectiveness of Additional Reductions in Cholesterol
and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL
cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors
of myocardial infarction: a double-blind randomised trial. Lancet 2010;
376: 1658-69. PubMed ID: 21067805. This trial demonstrated that
larger reductions in cholesterol, with a regimen of 80 mg
daily simvastatin, produced worthwhile further reductions in
CHD compared with a standard 20 mg daily regimen.
. Cholesterol Treatment Trialists' (CTT) Collaboration et al.
Efficacy and safety of more intensive lowering of LDL cholesterol: a
meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet
376, 1670-1681 (2010). PubMed ID: 21067804. A meta-analysis
showing that more intensive regimens of statins yield additional
benefits without any additional safety concerns.
. Cholesterol Treatment Trialists' (CTT) Collaborators et al.
The effects of lowering LDL cholesterol with statin therapy in people at
low risk of vascular disease: meta-analysis of individual data from 27
randomised trials. Lancet 380, 581-590 (2012). PubMed ID:
22607822. A meta-analysis showing definitively that the benefits of
statin therapy clearly outweigh the hazards in healthy people.
. Baigent, C. Landray MJ, Reith C, et al. The effects of
lowering LDL cholesterol with simvastatin plus ezetimibe in patients with
chronic kidney disease (Study of Heart and Renal Protection): a randomised
placebo-controlled trial. Lancet 377, 2181-2192 (2011).
PubMed ID: 21663949. The SHARP study from NDPH provided the first
reliable evidence that lowering cholesterol reduces the risk
of heart attacks and strokes among kidney patients.
The CTT Collaborative Group's work has been supported by funding from the
UK Medical Research Council, the British Heart Foundation, the European
Community Biomed Programme, the Australian National Health and Medical
Research Council and National Heart Foundation, and grants from Merck and
Details of the impact
Taken together, the CTSU's Heart Protection Study, Cholesterol Treatment
Trialists' Collaboration, SEARCH and SHARP studies have shown that
lowering low-density lipoprotein (LDL), or `bad' cholesterol with a statin
regimen, or a statin-based regimen, reduces the risk of heart attacks,
strokes and revascularisation procedures in both high-risk and healthy
people, and that more intensive statin regimens lead to further reductions
in risk. This work has influenced treatment guidelines and statin
medication labelling internationally. Given the known benefits of statins
on vascular mortality, and their widespread use, it is likely that CTSU's
work has contributed to the continuing decline in vascular mortality that
has been observed in developed countries over the past decade.
All the major national and international healthcare policy guidelines on
cardiovascular disease prevention have been influenced by CTSU's work on
cholesterol-lowering statin therapy. For example, the National Heart Lung
and Blood Institute's (NCEP) ATPIII North American guidelines [A], which
are the main guidelines used in the US, specifically refer to the Heart
Protection Study results. The UK National Institute of Health and Care
Excellence (NICE) guidelines on cardiovascular disease and statins [B],
and European Society of Cardiology guidelines for the management of
dyslipidaemias [C], refer to CTSU's trials (HPS and SHARP) as well as the
CTT meta-analyses throughout. By providing unique information about the
safety of simvastatin 80mg daily, the SEARCH study significantly
influenced both FDA [D] and MHRA [E] guidance on prescription of statins.
The SHARP results provide definitive evidence for the efficacy and safety
of a statin-based regimen for the prevention of atherosclerotic events
among patients with chronic kidney disease. The Kidney Disease Improving
Global Outcomes (KDIGO) group generates internationally recognised
guidelines for the care of kidney patients, and a KDIGO Work Group (in
which 5 of the 11 members were also members of the SHARP Steering
Committee) has recently published updated guidance for the use of
statin-based regimens that is based chiefly on the SHARP trial [F]. SHARP
has also strongly influenced other guidelines, including the Canadian
Cardiovascular Society (CCS) Guidelines for the Diagnosis and Treatment of
Dyslipidaemia [G], most particularly by helping to identify CKD as an
important risk factor for cardiovascular disease.
The NHS reports that there has been a 40% reduction in deaths from heart
disease in people under 75 since 2000, and estimates that statins
currently save around 7,000 lives a year in the UK [H]. CTSU's work on
ensuring that statin therapy is used appropriately widely has undoubtedly
contributed to this saving of lives during the REF 2014 period. Indeed,
NICE guidance throughout the REF period recommended the HPS regimen of
simvastatin 40mg as their first line treatment for cardiovascular disease
prevention in high-risk patients [B]. Due to the major public health
impacts of CTSU's research into the safety and benefits of statin use,
this work has also been featured prominently both on the internet and in
print versions of mainstream newspapers. Recent articles include publicity
surrounding the CTT's work on the effects of reducing cholesterol among
apparently healthy people, for example in the Daily Mail [I] and on the
effects of more intensive statin regimens in the Daily Telegraph [J].
Sources to corroborate the impact
[A]. ATP 3 Cholesterol Guidelines, NHLBI. nhlbi.nih.gov at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf
[Accessed 6th September 2013]
National Heart Lung and Blood Institute's (NCEP) ATPIII North
American guidelines on statin use, published in 2002 and still
current as of September 2013. See page II-61.
[B]. NICE Guidelines: Lipid modification: Cardiovascular risk assessment
and the modification of blood lipids for the primary and secondary
prevention of cardiovascular disease. http://www.nice.org.uk/nicemedia/live/11982/40742/40742.pdf
[Accessed 6th September 2013]
UK National Institute of Health and Care Excellence guidelines on
lipid modification quote the CTT Lancet meta-analysis widely
in their guidance. See pages 147, 168 (HPS), 166, 167, 168,
205, 206, 208 (CTT).
[C]. ESC/EAS Guidelines for the management of dyslipidaemias (2011) http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-dyslipidemias-FT.pdf
[Accessed 6th September 2013].
The European Society of Cardiology guidelines for the management of
dyslipidaemias. See pages 1792, 1806 (SHARP); 1783 (CTT)
[D]. US Food and Drug Administration website: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvide
rs/ucm204882.htm [Accessed 31st October 2013]. This
FDA guidance specifically refers to the SEARCH results in
relation to the risk of muscle injury with high dose statins.
[E]. Medicine and Healthcare products Regulatory Agency Drug Safety
Update Volume 3, Issue 10, May 2010. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169
[Accessed 31st October 2013]. This MHRA update comments
on the implications of the SEARCH results.
[F]. KDIGO Clinical Practice Guideline for Lipid Management in Chronic
Kidney Disease Kidney International Supplements (2013) 3, 261;
Lipid GL.pdf [Accessed 5th November 2013]. The
KDIGO guidelines are the main guidelines used internationally by
nephrologists, and this update is based chiefly on the results of
[G]. 2012 update of the Canadian Cardiovascular Society guidelines for
the diagnosis and treatment of dyslipidemia for the prevention of
cardiovascular disease in the adult. Can J Cardiol. 2013
Feb;29(2):151-67. doi: 10.1016/j.cjca.2012.11.032. PubMed ID 23351925.
These guidelines specifically refer to the SHARP results and
highlight the important role of CKD as a significant CV risk
[H]. NHS Choices. Coronary Heart Disease-Treatment. http://www.nhs.uk/Conditions/Coronary-heart-disease/Pages/Treatment.aspx
[Accessed 6th September 2013]. NHS Choices information
page, reporting statistics about reduction in Coronary Heart Disease
and statin use in the UK.
[I]. `All over-50s should take statins regardless of their health
history,' says Oxford professor | Mail Online 2012. dailymail.co.uk
[Accessed 6th September 2013].
Daily Mail article about CTSU's statin research featuring an
interview with Rory Collins.
[J]. More potent statins `could save thousands' — Telegraph 2010. http://www.telegraph.co.uk/health/8117635/More-potent-statins-could-save-thousands.html
[Accessed 6th September 2013]. Daily Telegraph article about CTSU's
statin research featuring an interview with Colin Baigent.