The primary objectives of the Heart Protection Study are to assess, in a wide range of patients at high risk of CHD to whom this might be importantly relevant, the effects during the scheduled treatment period of:
Secondary objectives include assessment of the effects of the study treatments on CHD mortality and morbidity in the first few years and later, and in various separate categories of patient; and assessment of their effects on the incidence of cancer, strokes, major vascular procedures and other conditions that require hospitalisation (see Section 2.5). The effects of the study treatments on cause-specific mortality and cancers during longer-term follow-up will also be assessed.
To avoid the uncertainties of interpretation that have affected the results of many previous prevention trials (and that may well also affect the other current studies of HMG CoA reductase inhibitors: see Section 1.3), the Heart Protection Study needs to be really large, to involve a substantial cholesterol reduction and substantial antioxidant supplementation, and to include patients who are at substantial risk of death within 5 years both from CHD and from other causes.
Patients with a history of coronary disease, occlusive disease of non-coronary arteries or diabetes mellitus are at particular risk of death from CHD. Large numbers of such patients are easily identifiable from general practice and hospital records. Consequently, many people could benefit if lowering cholesterol substantially can be reliably shown to produce a reduction of "only" about a quarter in CHD mortality in these "high-risk" patient categories (and in several other patient categories: e.g. male/female; old/young; hypertensive/normotensive; high/low baseline cholesterol; smokers/non-smokers). To be able to study CHD mortality reliably, a heterogeneous mixture of patients at high risk of death from CHD over the next 5 years will be invited to collaborate in the Heart Protection Study.
Invitation to the 40-50 Screening clinics for the study will be centrally coordinated from Oxford, with (i) over-sampling, where necessary, to ensure that sufficient numbers of patients in each of the various categories (i.e. type of prior disease; female; old; etc: but not cholesterol level since this would not be known prior to screening) are included to assess the effects of the study treatments directly in each category; and (ii) stratified randomisation to ensure even distribution between the different treatment groups with respect to important patient characteristics.
Epidemiological studies indicate that the proportional reduction in CHD risk associated with a particular prolonged absolute cholesterol difference is similar throughout the range above 3 mmol/l 1-7. Hence, cholesterol lowering may produce a greater absolute reduction in CHD mortality in a patient with "average" or "low" cholesterol but a high risk of death from CHD than in a lower-risk patient with "high" cholesterol (see Figure 3). Therefore, patients with cholesterol levels down to 3.5 mmol/l are eligible for the study provided that they are considered on the basis of other factors to be at substantial 5-year risk of CHD.
Some other current large reductase inhibitor trials have likewise included substantial numbers of patients with low baseline levels of total cholesterol (with, for example, about one-fifth of the patients in the North American NIH post-CABG and the Australasian LIPID trials having entry cholesterols of 5 mmol/l or less), as did the pilot study for the present study. No significant evidence has emerged after about 2-3 years follow-up in these studies that lowering cholesterol with reductase inhibitors in such patients is harmful. Even so, the Data Monitoring Committee will regularly review the interim results separately among such patients (see Section 2.5). By including patients at high risk of CHD but with "below-average" cholesterol levels, the Heart Protection Study will help to resolve uncertainties about the benefits, or otherwise, of lowering cholesterol in such patients. On its own, it may not include large enough numbers of patients with baseline cholesterol levels in the range 3.5 to 5.2 mmol/l for the effects on CHD incidence to be assessed separately in this subgroup, but the planned systematic overview of this and other trials should do so.
No upper limit of cholesterol is imposed in the Heart Protection Study since there may well be some patients, such as the elderly, in whom many clinicians are still substantially uncertain as to the benefits of lowering even an elevated cholesterol. Patients in whom a reductase inhibitor is considered by their own doctor to be clearly indicated (or clearly contraindicated) because of their cholesterol levels or for any other reason should not, of course, be randomised (see Section 3.1).
Eligible patients will be randomised in a 2 x 2 "factorial" design between:
The study treatment is conveniently calendar-packed, and is to be taken every evening for at least 5 years, unless some clear contraindication develops.
A "2 x 2 factorial" design assessing antioxidant supplementation will not prevent reliable assessment of the effect on mortality of lowering cholesterol with simvastatin (or vice versa). For, mortality among all the patients allocated active-simvastatin can still be compared with that among all those allocated placebo-simvastatin (even though half of each group will have received vitamins: Figure 4) 55.
The main assessment of the effects of simvastatin involves comparing the outcomes among all 10,000 allocated active-simvastatin (subtotal A) and among all 10,000 allocated placebo-simvastatin (subtotal B). Similarly, the main assessment of the effects of antioxidant vitamins involves comparing the outcomes among subtotals 1 and 2. Use of such a "factorial" design instead of a simple 2-way design just of simvastatin versus Placebo (or just of antioxidant vitamins versus placebo) has little or no effect on the statistical sensitivity with which the overall benefits of simvastatin (or of antioxidant vitamins) can be assessed, or on the total number of patients required in the study. Such a design does, of course, also allow (as a supplementary analysis) separate assessment of the benefit produced by simvastatin in the presence of antioxidant supplementation (i.e. (i) versus (ii)) and of the benefit produced by simvastatin in the absence of antioxidant supplementation (i.e. (iii) versus (iv)). Even if these two benefits are somewhat different, however, the main analyses of such a factorial trial still provide completely valid tests of whether there is any net effect on total mortality of simvastatin (and of antioxidant supplementation) that do not involve any implicit assumptions about interactions 55.
Previous studies in patients with angina, diabetes, carotid stenosis and peripheral vascular disease 20, 56-61 suggest that the overall 5-year CHD death rate would be about 9%, with about a further 5-6% dying from non-CHD causes. If so, and if simvastatin reduces 5-year CHD mortality by about 25% (and total CHD by about 35%), then a study of at least 20,000 such patients provides an excellent chance of demonstrating an overall effect on total mortality at a convincing level of statistical significance (Table 5). In any one of the three main categories of high-risk patients (coronary disease; occlusive disease of non-coronary arteries; diabetes mellitus), randomisation of about 6-7,000 patients should also allow reliable assessment of a reduction of about one quarter in fatal CHD with simvastatin. The study will, therefore, seek to randomise similar numbers in each of these three main high-risk categories, by "over-sampling" where necessary. Not only should this study provide separately significant evidence in the different risk groups, but also it should be sufficiently powerful for analysis of the effects on CHD within several other major subgroups, selectively including (i) about 6-7000 women, (ii) about 6000 elderly (age 65-75 at entry, and hence 70-80 after five years of treatment), and (iii) about 6000 with "normal" baseline cholesterol (3.5-6.0 mmol/l).
TABLE 5: Predicted numbers of events for the simvastatin comparison in the Heart Protection study of at least 20,000 high-risk individuals
|Allocated treatment||Power to detect*|
|Any one of three main high-risk categories|
|(e.g. 7000 diabetics, 1500 with prior MI)|
|Primary prevention (15,500 without prior MI)|
|Secondary prevention (4,500 with prior MI)|
|All 3 patient groups (20,000 high risk)|
*These and other comparisons all involve "intention-to-treat" logrank "first-event" analyses55, with exact variance calculations, of the numbers of affected patients.
The power of the study to detect effects of this size with antioxidant vitamins is as in Table 5. Indeed, such a study would yield a high degree of statistical significance even if antioxidant vitamins were associated with a reduction in the incidence of CHD of only about 10% (e.g. 1485 with a CHD event among controls versus 1336 among those allocated vitamins: 2P=0.003).
Reductase inhibitor therapy: the main comparisons will involve "logrank" analyses 55 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). The two main cause-specific analyses will be of (a) CHD mortality (ICD 410-414 in the 9th International Classification of Disease), and (b) non-CHD mortality. In addition, there will be separate analyses of ten specific causes, or groups of causes, of death: (i) haemorrhagic stroke (ICD 430-432), (ii) other stroke (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), (ix) suicide (950-959), and (x) other non-medical causes. Allowance for the multiple hypothesis testing in these ten analyses will involve a tenfold "Bonferroni" correction to the ten P-values.
Antioxidant vitamin supplementation: the main comparisons will involve "logrank" analyses of total CHD and of fatal CHD during the scheduled treatment period among all those allocated active-vitamins and all those allocated placebo-vitamins.
The principal subsidiary comparisons will be of the effects of simvastatin allocation and of vitamin allocation on (a) CHD rates in the first two years and in the later years of scheduled treatment to see if any protective effect increases with time, and on (b) cause-specific mortality rates not only during the scheduled treatment period but in long-term follow-up thereafter, to see if any benefits or hazards persist. (N.B. Total CHD is defined as non-fatal MI or fatal CHD.)
Other subsidiary comparisons will be made of the effects of simvastatin allocation and of vitamin allocation on fatal CHD and on total CHD in the following different circumstances:
In addition, the effects of simvastatin allocation on total non-CHD mortality will be assessed separately in the five groups of baseline cholesterol. Comparisons will also be made of the effects of each of the study treatments on the incidence of site-specific cancers, of total strokes, of confirmed cerebral haemorrhages, of vascular procedures (i.e. CABG, PTCA), and of hospitalisations for various causes. 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, with due allowance made for their exploratory (and, perhaps, data-dependent) nature 55.
During the period of the study, interim analyses of mortality and of any other information that is available on major events (including all serious adverse experiences, particularly among patients with low entry cholesterol levels), along with any other analyses that the committee may request, will be supplied regularly (and at least annually), in strict confidence, to the chairman of the independent Data Monitoring Committee. In the light of these analyses and the results of any other relevant trials (including those of the continuing pilot study, which already has more than 4 years of follow-up), the Data Monitoring Committee will advise the Steering Committee if, in their view, the randomised comparisons in the Heart Protection Study have provided both (a) "proof beyond reasonable doubt"* that for all, or for some specific types, of patient, really prolonged use of either treatment is clearly indicated or clearly contraindicated in terms of a net difference in all-cause mortality, and (b) evidence that might reasonably be expected to influence materially the patient management of many clinicians who are already aware of any other main trial results. The Steering Committee can then decide whether to modify the study (or to seek extra data). Unless this happens, the Steering Committee, the collaborators, the funding agencies and the central administrative staff (except those who supply the confidential analyses) will remain ignorant of the interim results on mortality and major morbidity. Reports on the biochemical effects of the treatment regimens being studied, similar to that produced for the pilot study 20, will, however, be made public during the study after about one year and three years of follow-up data are available.
Collaborators, and all others associated with the study, may write (preferably through the Oxford coordinating centre) to the chairman of the Data Monitoring Committee, drawing attention to any worries they may have about the possibility of particular side-effects, or about particular categories of patient requiring special consideration, or about any other matters that may be relevant.
Serious adverse experiences are defined as those which result in death or are life-threatening, produce a permanent or substantial disability, result in in-patient hospitalisation or the prolongation of such hospitalisation, or are cancer, congenital abnormality or the result of an overdose. Throughout the study, any serious adverse experiences that are believed with a reasonable probability to be due to study treatment are to be reported immediately by telephoning the 24-hour service at the coordinating centre (see Section 3.4). During this telephone call, standard information (i.e. identity of the patient and of the person reporting the event, nature and date of event, and their reason(s) for probable attribution to study treatment) are to be recorded directly on the coordinating centre computer. These reports will be reviewed immediately, blind to treatment allocation, by one of the clinical coordinators, and any further information required sought urgently. All such serious adverse experiences will then be promptly reported "unblinded" to the chairman of the Data Monitoring Committee and "blinded", by facsimile, to Merck Sharp & Dohme in Hoddesdon and to Hoffmann-La Roche in Welwyn. The companies will notify the coordinating centre if any further information is needed (including unblinding) and they will then forward such reports to any relevant drug regulatory agencies.
Serious adverse experiences that are not thought to be due to study treatment are not required to be reported in this way. All such events will, however, be routinely recorded on the Follow-up Forms and will be monitored centrally as the study progresses.
The Clinical Trial Service Unit (CTSU) at Oxford University is coordinating the Heart Protection Study. It is responsible for the training and monitoring of all staff directly involved in the study; for the supply of conveniently packaged study drugs and other study materials; for the invitation of suitable identified patients to each clinic (in the name of the local medical collaborator); for the allocation of Screening and subsequent clinic appointment times (and notification of this schedule to each hospital in advance); for the provision of a 24-hour Freefone telephone service (for appointment changes, central randomisations, urgent queries, unblinding where medically necessary, and reporting of any serious adverse experiences believed to be due to study treatment); and for the collection and analysis of data and blood samples. (This is summarised below, and is described in detail in the Hospital Manual and in the coordinating centre operating procedures.)
Training and monitoring: Clinic staff will be advised by the Oxford coordinating centre on methods for identifying and screening potentially eligible patients, and will be trained in correct study clinic procedures (as summarised in Section 3 of the protocol and described in detail in the Hospital Manual). Coordinating centre staff will visit each collaborating hospital 2-3 times during the first year of the study to discuss the study rationale and design with relevant clinical and other staff, to assist in the setting up of study clinics, and to monitor the conduct of the clinics during the Screening and Randomisation phases. Subsequently, 1-2 visits will be made each year to monitor the clinics. The coordinating centre staff will also arrange regular meetings of all collaborators to discuss the progress of the study and other general issues, and to provide an update on the results of any other relevant studies. The Oxford coordinating staff will maintain regular telephone contact with the local clinic staff and medical collaborators between visits and meetings. Collaborators and clinic staff will also be encouraged to contact the coordinating centre office (or 24-hour service for urgent queries) if they wish to discuss some problem or other issue related to the study.
Supply of study materials: Equipment required for the study clinics (e.g. Accutrend desk-top blood analysers for the preliminary cholesterol analysis at Screening, facsimile machines for rapid communication with the coordinating centre, etc) and all consumables (e.g. study manuals and forms, stationery, blood-taking equipment, etc) will be provided by the Oxford coordinating centre. All study medication will be supplied in treatment packs containing the appropriate number of calendar blister-strips for each period of the study. Any study drug not required by participating patients is to be collected by clinic staff and returned at regular intervals to the coordinating centre for disposal.
Data handling: The Oxford coordinating centre will help in the identification of potentially eligible patients from hospital and health authority records. The coordinating centre will use this information to generate invitations, in the names of the local medical collaborators, for patients to attend the local study clinics (see Section 3.1). The top copies of all completed and signed clinic forms (except those Screening Forms with consent pending: see Sections 3.2 to 3.4) are to be sent to the Oxford coordinating centre at the end of each clinic day (with the middle copies kept in the patients' study files in each hospital and the bottom copies used for pharmacy records, if required). The information on these forms will be visually checked and coded by the coordinating centre staff, and then entered on computer (following an operating procedure for data handling, in accordance with Good Clinical Practice guidelines). Any missed Follow-up clinic appointments identified by the coordinating centre will result in checks that the study nurse has arranged another appointment (or, if the patient is no longer willing to attend clinic, that a telephone follow-up will be conducted). Errors in the completion of study forms detected by the coordinating centre will result in computer-generated correction requests being sent to the clinic staff, with all such corrections to the data being entered on the central computer. The coordinating centre is responsible for seeking confirmation and additional information about any relevant clinical events reported during follow-up, and for obtaining details from national registries of any deaths or non-fatal cancers among study patients (see Section 3.5).
Laboratory: Blood samples taken by the clinic staff will be picked up by couriers at the end of each clinic day for overnight delivery to the coordinating centre laboratory in Oxford. The central laboratory will use part of each blood sample for immediate assays, with the remainder of certain samples being frozen for subsequent assays (see Sections 3.2 to 3.4). The laboratory uses a number of internal and external quality control procedures and follows a standard operating procedure, in accordance with Good Laboratory Practice guidelines. Checked assay results will be transferred to the central computer and linked to the patient's other data. The coordinating centre will inform the patient's general practitioner, and the clinic staff, of the routine Screening results (see Section 3.2). Subsequently, biochemical abnormalities requiring action will be reported back to the clinic staff and, in such cases, appropriate Early Recall visit arrangements will be made with the patient by the coordinating centre (see Section 3.4).
Source documents and archiving: The lists of potentially eligible patients provided to the Oxford coordinating centre, the clinic forms, the computer-generated error forms, the additional information obtained on reported outcome measures and other relevant events, the death certificates, the blood assay results and the drug supply records constitute the "source documents" for the study. The coordinating centre will retain these data and records for at least 15 years. The sponsors and regulatory agencies will have the right, in accordance with Good Clinical Practice guidelines, to commission a confidential audit of such records kept in the coordinating centre and in the collaborating hospitals, as long as this does not result in unblinding of the interim results while the study is still in progress.
About 40-50 hospitals each randomising about 500 patients: In planning for a large mortality study in different categories of high-risk patient, a randomised placebo-controlled pilot study of simvastatin has been conducted by CTSU in 600 patients 20. This experience indicates that for each collaborating hospital to randomise 500 patients in the main study only about 1500 potentially eligible patients need to be invited to a Screening clinic. This should yield about 1000 clinic attendees who could then be screened over an 18-month period in the equivalent of about six 3-hour clinic sessions each week. Subsequent follow-up during the next 5 years of the 500 randomised patients this would yield requires only about three 3-hour clinic sessions weekly. About 40-50 collaborating hospitals (or equivalent, since a hospital might well be able to randomise more than 500 patients) should be able to randomise and follow up at least 20,000 high-risk patients.
Setting up study clinics: The medical collaborator in each hospital is responsible, with the help of the Oxford coordinating centre, for obtaining local ethics committee approval; for appointing and overseeing the clinic staff; and for ensuring that adequate clinic and reception space is available. The equivalent of a full-time experienced nurse (or two half-time nurses) is required for the identification of over 1500 patients and the screening of about 1000 patients in each centre during the first 18 months, with the equivalent of a part-time receptionist/secretary covering the hours of clinic time to ensure efficient running of the Screening programme (including confirmation of personal details and appointments, and handling paper work). During the follow-up period, the equivalent of a half-time nurse would be able to see 500 randomised patients at 4-monthly intervals in the first year and subsequently at 6-monthly intervals to monitor and deal with any possible adverse drug effects, to record any clinical study end-points, and to encourage compliance.
The study is being funded by the UK Medical Research Council, the British Heart Foundation, Merck Sharp & Dohme (the manufacturers of simvastatin), and Hoffmann-La Roche (the vitamin manufacturers). It was, however, designed independently of the pharmaceutical companies, who have no representative in its organisation and who will, like the Steering Committee, remain blind to the main results as they accumulate. This arrangement is intended to ensure that no suggestions of lack of objectivity of the findings can be justified. The study has been designed to comply with the principles of the Declaration of Helsinki (as amended in 1989).
The pharmaceutical companies that are participating in the study will indemnify, and hold harmless, any institution or individual collaborating in the study from and against any and all claims or law suits resulting from participation, provided that (i) those seeking indemnity have not departed in any importantly relevant manner from compliance with the protocol, and provide all reasonably possible assistance to the pharmaceutical companies in defence of such claims (allowing the companies, if they wish, to settle the claim or take over the defence), and (ii) the companies will not be liable for any injuries resulting from medical negligence. In the absence of any other arrangements, the Medical Research Council will give sympathetic consideration to claims for compensation against collaborating individuals and institutions for any harm suffered as a result of participation in the study. These MRC arrangements are fully in accord with the recommendations of the Medicines Commission and with the Department of Health's 1991 advice to local research ethics committees.
The success of this study depends entirely on the wholehearted collaboration of a large number of doctors and nurses. For this reason, chief credit for the main results will be given not to the central organisers, but to all those who have collaborated in the study.HPS * Front Cover * Contents * Section 1 * Section 2 * Section 3 * Appendix * References * Back Cover