Data Analysis Plan:
Main and
subsidiary assessments
of outcome in the MRC/BHF Heart Protection Study
(updated September 2001)
Primary (main) comparisons
Reductase inhibitor
therapy: the
primary comparisons will involve "logrank" analyses of total mortality
and of cause-specific mortality during the scheduled treatment period
among all those allocated active-simvastatin versus all those allocated
placebo-simvastatin (i.e. "intention-to-treat" analyses)1,2. The two main cause-specific
analyses will be of (a) CHD mortality (ICD 410-414 in the 9th International
Classification of Diseases), and (b) non-CHD mortality.
Antioxidant vitamin
supplementation: the primary comparisons will involve "logrank"
analyses of total CHD and of fatal CHD during the scheduled
treatment period among all those allocated active-vitamins versus all those
allocated placebo-vitamins. (N.B. Total CHD is defined as definite/probable*
non-fatal MI or fatal CHD.)
All time-to-event analyses
will
be based on the first relevant event. No allowance will be made for multiple
hypothesis testing in the primary comparisons of each of the study treatments.
Conventionally, in the final analyses of primary comparisons, two-sided
P-values (2P) <0.05 are often described as "significant". But, in
interpreting such findings it is necessary to consider whether they are
supported by evidence on relevant non-fatal events. Moreover, the larger the
number of events on which a comparison is based and the more extreme the
P-value (or, analogously, the further the lower limit of the confidence
interval is from zero), the more reliable the comparison and, hence, the more
definite any finding1,2.
Secondary comparisons
Separate analyses of the
effects
of simvastatin allocation on ten specific causes, or groups of causes, of
death: (i) haemorrhagic stroke (including intracerebral and subarachnoid
haemorrhage: ICD 430-432); (ii) other stroke (including ischaemic and
uncertain aetiology: 433-438); (iii) other vascular (rest of 390-459); (iv)
neoplastic (140-239); (v) respiratory (460-519); (vi) hepatic (570-576);
(vii) renal (580-593); (viii) other medical causes (rest of 000-799:
including definitely unknown causes); (ix) suicide (950-959); and (x) other
non-medical causes. In interpreting these results, allowance will be made for
the multiple hypothesis testing in these ten analyses, for the effects observed
on relevant non-fatal events, and for evidence from other studies.
The effects of simvastatin
allocation and of vitamin allocation on: (i) total CHD rates in the first two
years and in the later years of scheduled treatment to see if any protective
effect increases with time (i.e. comparison of effect during years 1-2 with
that during years 3+); (ii) cause-specific mortality rates (i.e. deaths from
CHD and deaths from non-CHD, as defined above) not only during the scheduled
treatment period but in long-term follow-up thereafter, to see if any benefits
or hazards persist; and (iii) total (i.e. fatal and non-fatal) stroke and,
separately**, presumed ischaemic stroke (i.e. all strokes not confirmed to be
haemorrhagic) during the scheduled treatment period.
The effects of simvastatin
allocation and of vitamin allocation on total CHD, and on "major vascular
events" (defined as total CHD, total stroke and coronary or non-coronary
vascular procedures), in the following different circumstances:
(i) in different categories of prior disease: MI; other
CHD;
and no CHD (cerebrovascular; peripheral vascular; diabetes mellitus; treated
hypertension: considered together and separately)*;
(ii) in various other categories determined at Screening:
(a) men and women;
(b) age (years):
<65;
>=65<70;
>=70*
(c) diastolic blood pressure (mmHg): <80;
>=80<90;
>=90*
(d) systolic blood pressure (mmHg):
<140;
>=140<160;
>=160*
(e) total cholesterol (mmol/l): <5.0;
>=5.0<6.0;
>=6.0*
(f) HDL-cholesterol (mmol/l): <0.9;
>=0.9<1.1;
>=1.1*
(g) LDL-cholesterol (mmol/l): <3.0;
>=3.0<3.5;
>=3.5*
(and, as a tertiary comparison, <100;
>=100<130;
>=130 mg/dl will also be
considered**)
(h) apolipoprotein A1
(mg/dl): <110;
>=110<130;
>=130**
(i) apolipoprotein B (mg/dl): <100;
>=100<120;
>=120**
(j) triglycerides: <2.0;
>=2.0<4.0;
>=4.0**
(k) creatinine (µmol/l): "normal" (<130 men;
<110
women); "elevated"
(l) smoking: never regular smoker; ex-cigarette smoker;
current smoker*
(m) alcohol (drinks/week): none; 1-21;
>=22**
(n) body mass index (kg/m2):
"lean" (<25 male / <24 female); "overweight"
>=25<30 male /
>=24<28 female);
"obese" (>=30 male
/ >=28 female)**
(o) waist (cm): "normal" (<94 male / <80
female);
"increased" (>=94<102
male />=80<88 female);
"excessive" (
>=102 male / >=88 female)**
(p) non-diabetic patients with and without the "metabolic
syndrome" (defined as "excessive" waist measurement, plus HDL
<=
1.0 mmol/l for men or <=1.3 mmol/l for women, plus
SBP >=135 mmHg or DBP
>=85 mmHg).
(q) HbA1C (%)
among
patients with diabetes: <7.0; >=7.0
(r) vitamin E (µmol/l): <24;
>=24<30;
>=30*+
(s) vitamin C (µmol/l): <40;
>=40<60;
>=60*+
(t) beta-carotene (µmol/l): <0.24;
>=0.24<0.40;
>=
0.40*+
(iii) in the presence and the absence of the other study
treatment;
and
(iv) among patients subdivided into 3 similar-sized groups with
respect to the size of the reduction in blood cholesterol and the size of the
increase in vitamin levels+,
respectively, during the pre-randomisation Run-in period.
The very large numbers of
patients in this trial may allow reasonably reliable direct assessment
of the effects of the treatments on common outcomes in some major subcategories
of patient. But, when a number of different subgroups are considered, chance
alone may lead to there being no apparent effect in several small subgroups in
which treatment really is effective. In such circumstances, "lack of
direct evidence of benefit" is not good "evidence of lack of
benefit", and clearly significant overall results would provide strong
indirect evidence of benefit in some small subgroups where the results,
considered in isolation, are not conventionally significant (or even, perhaps,
slightly adverse). Hence, unless the proportional effect of treatment in some
specific subcategory is clearly different from that observed overall
(including, for example, in the presence and absence of the other study
treatment), the effect in that subcategory is likely to be best estimated indirectly
by applying the proportional effect observed among all patients in the trial to
the absolute risk of the event observed among control patients in that category3. Tests for heterogeneity of the proportional
effect observed in subgroups will be used (with allowance for multiple
comparisons) to determine whether the effects in specific subcategories are
clearly different from the overall effect
1,2.
If, however, patient categories can be arranged in some meaningful order (e.g.
baseline total cholesterol: <5.0;
>=5.0<6.0;>=6.0*) then assessment of
any trend in the proportional effects would be made. Moreover, based on the
differences in LDL-cholesterol observed during follow-up between all those allocated
active-simvastatin and all those allocated placebo-simvastatin (i.e.
irrespective of compliance), LDL-weighted analyses will be used to estimate the
effects of actual compliance with simvastatin on total CHD in different
circumstances (as well as the overall effects on fatal CHD, on total stroke and
on other relevant outcomes)4.
Tertiary comparisons
The effects of simvastatin
allocation and of vitamin allocation on fatal CHD and on total stroke will be
assessed separately during years 1-2 and years 3+ of follow-up, and in the
different circumstances described under paragraphs (i) to (iv) of the Secondary
Comparisons section**. These results will be interpreted in the context of the
results of the parallel analyses of total CHD, with allowance made for multiple
hypothesis testing. The effects of simvastatin allocation on total non-CHD
mortality will also be assessed separately in the three pre-defined groups of
baseline total cholesterol*.
In addition, the tertiary
comparisons will include assessment of the effects of simvastatin allocation
and of vitamin allocation on:
(i) site-specific cancers;
(ii) confirmed cerebral haemorrhage (excluding
subarachnoid
haemorrhage); and, separately**, subarachnoid haemorrhage;
(iii) coronary vascular procedures (i.e. CABG, PTCA); and
non-coronary vascular procedures (i.e. carotid endarterectomy or angioplasty,
other arterial grafts or angioplasty and amputation)*;
(iv) hospitalisations for angina; hospitalisations for
respiratory disease; and hospitalisations for gallbladder disease (e.g.
gallstones, cholecystectomy, biliary surgery) other than cancer*;
(v) days spent in hospital for: (a) any CHD event; (b)
other
vascular events; and (c) the aggregate of all other reasons**;
(vi) fractures of any kind; and fractures of hip, wrist or
spine
combined (excluding, in both cases, those due to road traffic accidents)**;
(vii) cognitive function: based on difference at final
follow-up
in TICS-m score, with cognitive impairment defined as <22 out of 39, among
(a) all patients; and (b) those who have never had a stroke**;
(viii) respiratory function: based on difference at final
follow-up in (a) forced expiratory volume in 1 second (FEV1), and (b) forced vital capacity
(FVC)**;
(ix) among diabetics at study entry, peripheral macrovascular
complications (defined as lower limb amputation plus peripheral arterial
revascularisation procedure plus leg ulcers).
(x) development of diabetes: based on reported diabetes
and/or
use of insulin or oral hypoglycaemic drugs by final follow-up among patients
not known to be diabetic at baseline**;
(xi) angina severity: based on the change in angina score
between baseline and final follow-up**.
Among a sample of the
diabetics,
the effects of simvastatin on changes from baseline of HbA1C and of creatinine will be assessed.
Many other analyses will be performed and presented (e.g. hospitalisations for
various different causes), with due allowance for their exploratory (and,
perhaps, data-dependent) nature.
1 Peto
R, Pike MC, Armitage P et al. Design and analysis of randomized clinical
trials
requiring prolonged observation of each patient. Part I: Introduction and
design. Br J Cancer 1976; 34: 585-612
2 Peto
R,
Pike MC, Armitage P et al. Design and analysis of randomized clinical trials
requiring prolonged observation of each patient. Part II: Analysis and
examples. Br J Cancer 1977; 35: 1-39
3
Collins
R, MacMahon S. Reliable assessment of the effects of treatment on mortality
and major morbidity, I: clinical trials. Lancet 2001; 357: 373-80
4 Cuzick
J, Edwards R, Segnan N. Adjusting for non-compliance and contamination in
randomized clinical trials. Stat Med 1997; 16: 1017-29
Modifications/clarifications* or additions** to previously
pre-specified analyses agreed, blind to treatment-related results, following
discussions at the March 2001 Steering Committee meeting. Pre-specified
analyses within categories determined by baseline vitamin levels+ are intended for assessment of the
effects of vitamin allocation (and not for those of simvastatin allocation).