Independent Analyses of the SEAS, SHARP and IMPROVE-IT Studies of Ezetimibe

London (ots/PRNewswire) - The University of Oxford Clinical
Trial Service Unit and Epidemiological Studies Unit (CTSU) proposed
that the hypothesis-generating results of the SEAS trial of ezetimibe
should be tested by reviewing the combined cancer results from the
SHARP and IMPROVE-IT trials of ezetimibe, and reporting on the
overall findings to the relevant regulatory authorities,
independently of the drug manufacturers.

The two hypothesis-testing trials (SHARP and IMPROVE-IT) contain
about four times as many cancers as the SEAS trial. They do not
confirm the hypothesis raised by the SEAS trial that treatment
increases the overall risk of developing cancer. In addition, there
is no increase with time in the relative risk (active vs placebo)
suggested by the cancer incidence and mortality from all 3 trials
together (or just from the pair of hypothesis-testing trials).
Consequently, the SEAS, SHARP and IMPROVE-IT trials do not provide
credible evidence of any adverse effect on cancer.

Allocation to 5 years of substantial LDL-cholesterol lowering by
a statin has been shown previously to have no apparent effect on
cancer. The Cholesterol Treatment Trialists' collaboration has
published results (Lancet 2005;366: 1267-78) based on 90,000 patients
randomised evenly between statin and control. Based on 5530 patients
with cancer onset after randomisation, the statin vs control relative
risk was 0.997 (with 95% confidence interval 0.95-1.05; not
significant). Of these patients, 2163 died of their cancer during the
scheduled follow-up period; the relative risk for cancer death was
1.01 (with 95% confidence interval 0.91-1.12; not significant).

In the final results from the SEAS trial, there appears to be a
small increase in total cancer incidence in the group allocated
ezetimibe + statin, but this is based on only 102 vs 67 cancer cases
(including 39 vs 23 fatal cases) and there is no significant increase
in any particular type of cancer.

Two other large trials of ezetimibe + statin are still in
progress: (i) SHARP (ezetimibe + simvastatin vs placebo in 9,000
patients; recruitment completed, but treatment and follow-up
continuing) and (ii) IMPROVE-IT (ezetimibe + simvastatin vs placebo +
simvastatin in 11,000 patients; recruitment continues towards an
eventual target of 18,000 patients). Together, they have already
accumulated about four times as many cancers as SEAS (see table). If
treatment really did increase total cancer by 50% then this would
have been clearly apparent in the hypothesis testing SHARP &
IMPROVE-IT trials. Instead, there was no evidence of any increase in
cancer (see table).

Cancer events Active Control
Hypothesis generator: SEAS 102 67
Hypothesis test: SHARP & IMPROVE-IT* 313 326
* 216 active vs 254 control non-fatal cases and 97 vs 72 fatal cases.

If there were a real adverse effect on cancer incidence or cancer
mortality then previous experience with the epidemiology of cancer
(ie, with other causes of the disease in humans) strongly suggests
that the relative risk (active versus control) should grow bigger
with time, but it does not, whether the hypothesis-testing trials are
considered separately or all 3 trials are considered together.

Note: The University of Oxford Clinical Trial Service Unit and
Epidemiological Studies Unit (CTSU) has decades of experience in
cancer epidemiology, in vascular and other trials, and in
collaborative meta-analyses of trials. Although CTSU is conducting
the SHARP trial, it is doing so independently of the source of
funding, and has a policy of not accepting honoraria or consultancy
fees. This report to regulatory authorities on the analyses of SEAS,
SHARP and IMPROVE-IT was initiated, conducted and interpreted by the
CTSU independently of any source of funding.

For more information, please, refer to the press release issued
by the SEAS investigators today.

Contact: Andrew Trehearne, CTSU, +44(0)1865-743960,
+44(0)789-404-2600

Co-directors: Rory Collins FMed Sci FRCP BHF Professor of
Medicine and Epidemiology Sir Richard Peto FRS Hon FRCP Professor of
Medical Statistics and Epidemiology

Jane Colin Jillian John Cairns Zhengming Michael
Armitage Baigent FFPH Boreham FRS Chen MBBS Clarke DPhil
FFPH FRCP FRCP PhD DPhil
Emeritus Professor of
Reader in Professor of Senior Professor Professor of Clinical
Clinical Epidemiology Research of Cancer Epidemiology Epidemiology
Epidemiology Fellow
Robert Sarah Darby Christina Alison Martin Christine
Clarke FFPH PhD Davies Halliday Landray PhD Marsden PhD
FRCP BMBCh MSc FRCS MRCP
Professor of Unit
Reader in Medical Senior Consultant Reader in Administra-
Epidemiology Statistics Research in Vascular Epidemiology tor
Fellow Surgery
Sarah Parish Max Parkin Susan David Alan Young Sarah Clark,
DPhil MD Richards Simpson OBE DPhil Karen
DPhil Hon MFPH Kourellias &
Senior Honorary Head of
Research Senior Senior Director, Systems Martin
Fellow Research Research IATH Development Radley: Lab
Fellow Fellow Management

ots Originaltext: University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit
Im Internet recherchierbar: http://www.presseportal.de

Contact:
Contact: Andrew Trehearne, CTSU, +44(0)1865-743960,
+44(0)789-404-2600