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

    LONDON, July 21 /CNW/ - 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.

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

    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

For further information:

For further information: Andrew Trehearne, CTSU, +44(0)1865-743960,

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