HPS * Front Cover * Contents * Section 1 * Section 2 * Section 3 * Appendix * References * Back Cover

(see Hospital Manual for details)





FOLLOW-UP CLINIC VISITS at 4, 8, & 12 months, then 6 monthly



Eligibility for the study

Men or women aged about 40-75 are eligible to be invited into this study, provided they have:

  1. High risk of CHD over the next 5 years: The patient is considered to be at substantial risk of coronary heart disease over the next 5 years, based on 3 main categories of past medical history:

    1. Coronary disease: definite or probable clinical diagnosis of MI, unstable angina, stable angina, PTCA or CABG;
    2. Occlusive disease of non-coronary arteries: clinical, angiographic or ultrasound diagnosis of carotid artery stenosis (e.g. TIA or non-disabling stroke not thought to be haemorrhagic), carotid endarterectomy, leg artery stenosis (e.g. intermittent claudication) or surgery; or
    3. Diabetes mellitus: clinical diagnosis of insulin-dependent or maturity-onset diabetes.

    (N.B. If MI, stroke or hospitalisation for angina has occurred within the previous six months, then an otherwise eligible patient may be invited for a later repeat of the Screening visit.)

  2. No clear indications for the study treatments: The patient is not already taking HMG CoA reductase inhibitors or high-dose vitamin E supplements, and neither the patient nor the patient's doctor considers there to be any definite need to do so.
  3. No clear contraindications to the study treatments: Neither the patient, nor the patient's doctor, nor the study clinic staff considers there to be any contraindications to HMG CoA reductase inhibitors (or the vitamin supplements). Contraindications include:

    1. baseline plasma cholesterol <3.5 mmol/l;
    2. chronic liver disease (i.e. cirrhosis or hepatitis) or abnormal liver function (i.e. ALT >1.5 x upper limit of normal [ULN]);
    3. severe renal disease or evidence of renal impairment (i.e. creatinine >2xULN);
    4. inflammatory muscle disease (such as dermatomyositis or polymyositis) or CK >3xULN;
    5. concurrent treatment with cyclosporin (or a condition likely to result in organ transplantation and the need for cyclosporin);
    6. concurrent treatment with fibrates or high-dose niacin. (N.B. Patients on cholesterol-lowering diets or drugs – other than HMC CoA reductase inhibitors, fibrates or high-dose niacin – can still be entered in the study);
    7. child-bearing potential (i.e. pre-menopausal woman who is not sterilised or using a reliable method of contraception).
  4. No other predominant medical problem: The patient does not have some condition (other than a high risk of CHD) that might limit compliance with 5 years of study treatment:

    1. a recent history of alcohol or drug abuse;
    2. psychiatric disorder, senility, or physical disability (such as severely disabling stroke);
    3. severe heart failure (i.e. causing shortness of breath at rest) or some importantly life-threatening condition other than vascular disease (i.e. life-expectancy of less than 5 years: such as, very severe chronic airways disease or cancer other than non-melanoma skin cancer).
No upper limit of cholesterol is imposed 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. If the patient's doctor definitely wants to use an HMG CoA reductase inhibitor or high-dose vitamin E supplements in a particular patient then they should do so, and the patient would not be randomised. But, if they are uncertain as to whether or not to use such treatments then the patient should be considered for randomisation.

Identification and invitation of potentially eligible patients to Screening Clinics

Records of patient discharges kept centrally by health authorities and collaborating hospitals, and records kept for special wards (e.g. the coronary care unit) or for special clinics (particularly those concerned with vascular diseases or procedures, or with diabetes) are to be used to identify potentially eligible patients for the study. Lists of these patients are to be provided to the Oxford coordinating centre, which will seek agreement (in the name of the local medical collaborator) from patients' general practitioners to invite patients to the local study clinic. The coordinating centre will then invite (in the name of the local medical collaborator) potentially eligible patients to attend specific appointments in the Heart Protection Study Screening clinic at the collaborating hospital. Patients will be asked to confirm their attendance or, if they wish, to change their appointment by telephoning the coordinating centre on a 24-hour Freefone number. An updated schedule of clinic appointments will be sent regularly from the coordinating centre to each collaborating hospital.


Relevant medical history, physical examination and blood samples

For all patients attending the Screening visit, the relevant past medical history and other factors relevant to eligibility and CHD risk are to be recorded by the clinic nurse on the Screening Form. The clinic nurses are to check the study inclusion and exclusion criteria, and to record blood pressure, weight and height. A non-fasting blood sample is to be taken, and part used for an immediate (preliminary) measurement of cholesterol by Accutrend desk-top analyser. All Screened patients are to be given dietary advice similar to that contained in the American Heart Association stage 1 diet guidelines and other personalised information about modification of risk factors for vascular disease. Any noteworthy conditions identified at Screening that might require further investigation or treatment may be brought to the attention of the patient's own doctors by the clinic staff.

Invitation to participate in the randomised study and patient consent

Those patients who appear to be eligible for the randomised study are to be given the information leaflet (see Appendix) and to have the study explained to them by the clinic nurse. Patients should have an opportunity to initiate any discussion they wish during the initial Screening visit, and have time to think about the invitation to participate in the study – perhaps discussing it first with their family or general practitioner – before making a final decision. (Eligible patients who wish to do this will be asked to attend a Consent Pending visit about one week later.) All patients who agree to participate should be asked for their written consent in a form acceptable to the local ethics committee. Patients should be discouraged from participating if it is unlikely that they would be willing and able to continue attending the Follow-up clinics for at least 5 years.

Run-in period prior to randomisation

Those patients who agree to participate are to be given a Run-in treatment pack. This contains a 10-week calendar-blister supply of study treatment: the first 4 weeks' supply of this Run-in period consists of red calendar-blisters of placebo-simvastatin and active-vitamins (to give time for the laboratory check of liver enzymes, creatinine and CK), followed by 4-6 weeks of silver calendar-blisters containing both active treatments (to allow assessment of their effects on blood cholesterol and vitamin levels). An appointment for the patient to attend a Randomisation visit should then be arranged for about two months later. Patients will be told to telephone the 24-hour service at any time during the study to change their appointment if it is inconvenient, or to make an earlier appointment if they are having any problems. (Those on oral anticoagulants will also be advised to have their anticoagulant dose checked by their general practitioner after starting the silver calendar-blisters.)

At the end of each clinic day, blood samples from patients starting Run-in treatment (and from those with consent pending), along with all visit forms, are to be sent by courier to the coordinating centre for immediate laboratory assay (lipid profile, ALT, gamma glutamyl transaminase, creatinine, CK and, in diabetics, HbA1c), and for storage in liquid nitrogen for subsequent analyses (including antioxidants). The general practitioner of each patient started on Run-in treatment will be informed of their patient's Screening lipid profile and other blood results by the coordinating centre (and for patients on oral anticoagulants, will be advised to check prothrombin times as these can increase with reductase inhibitor therapy and with vitamin supplementation). This will allow the patient's own doctor to decide, during the 2-month Run-in period prior to randomisation, whether they wish to prescribe a reductase inhibitor or high-dose vitamin supplements (or, conversely, consider such treatment to be clearly contraindicated), in which case that patient is not to be randomised. Patients in whom significantly abnormal Screening blood results are identified by the central laboratory will be contacted during the placebo- simvastatin phase of Run-in and advised to stop taking the study treatment and to return the remaining treatment to the coordinating centre.

The Run-in period of about 2 months prior to randomisation is to help ensure that only those likely to continue taking study treatment for an extended period are randomised. Any patients who have any apparent side-effects to treatment, who appear to be non-compliant or who wish to drop out for any reason during this Run-in period are not to be randomised. Patients are to be randomised (see below) only if, at the end of Run-in, they seem likely to comply with the study protocol for several more years. By this process, many potential drop-outs should be excluded before becoming part of the randomised comparison, with a consequent improvement in statistical sensitivity.


Final check of eligibility and compliance before randomisation

Patients who attend their Randomisation clinic appointment at the end of the 2-month Run-in period should be asked if they have suffered MI, stroke, hospitalisation for unstable angina or any other significant problems during the Run-in period. Details are to be recorded on the Randomisation Form, and compliance with taking Run-in treatment checked (i.e. about 90% or more of the scheduled study treatment should have been taken: all remaining Run-in medication is to be retrieved and returned at regular intervals to the coordinating centre). All non-study treatments taken regularly by the patient are to be recorded. Compliant patients who have not had a major vascular event or other significant problem during the Run-in period (and are not on a contraindicated drug) are to be asked if they are still willing to continue taking study treatment for at least the next 5 years. If they are, a non-fasting blood sample is to be taken for immediate central laboratory assay (lipid profile, ALT and creatinine), and for storage in liquid nitrogen for subsequent analyses (including antioxidants).

The central 24-hour randomisation service at the coordinating centre (CTSU, Oxford) is then to be telephoned:

0800-585323 (Freefone) or 01865-240972

This telephone call allows the coordinating centre to check that sufficient information has been obtained for long-term follow-up through central government records, and provides an opportunity:

  1. to conduct a final check of eligibility prior to randomisation;
  2. to stratify the randomisation with respect to important patient characteristics (in particular, eligibility criteria and other major prognostic factors: see Section 2.5), ensuring even distribution between the different treatment groups; and
  3. to ensure that the types of patients studied can be characterised.

Treatment allocation

After a few brief details have been provided, a treatment pack number is to be specified and this is to be recorded on the Randomisation Form. An appointment is also to be made during this telephone call for the first post-randomisation Follow-up clinic visit in about 4 months, and this is also to be recorded on the Randomisation Form. The patient is then to be given the correct numbered Randomisation pack containing sufficient calendar-blisters of simvastatin (one 40 mg tablet every evening) or matching placebo tablets, and of vitamins (two capsules every evening, each containing 300 mg vitamin E, 125 mg vitamin C, and 10 mg beta-carotene) or matching placebo capsules. The patient's general practitioner will be informed of their patient's randomisation (and, for patients on oral anticoagulants, will be advised to check prothrombin times again).


Follow-up visits at 4, 8 & 12 months and then at 6-monthly intervals

After randomisation, patients are to be seen in the clinic for routine Follow-up checks for cardiovascular events and any other serious adverse events, first at 4, 8 and 12 months post-randomisation, and then at 6-monthly intervals. Details are to be recorded on the Follow-up Form of the main reason(s) for all hospital admissions (including day cases) and of any suspected myocardial infarctions, strokes, coronary angioplasty, coronary artery or other vascular surgery, cancer, or other serious adverse experiences. Any new unexplained muscle pain or weakness and regular non-study treatment is also to be recorded. Compliance with taking the study treatment is to be checked and, for patients who stop this treatment, the reason(s) for doing so recorded. (Any study drug not required by patients is to be retrieved and returned at regular intervals to the coordinating centre.)

At each Follow-up visit, a non-fasting blood sample is to be taken for immediate central laboratory assay of ALT (and CK, if significant new unexplained muscle pain or weakness is reported). Each year, a small random sample of these blood samples will be analysed in detail and stored in liquid nitrogen for subsequent analyses (see Section 3.5). Patients are then to be given a further supply of their study treatment and encouraged to keep taking it every evening for the duration of the study. An appointment should then be arranged for the next scheduled clinic visit. Clinic staff in any doubt about an individual patient's management should discuss it either with the local medical collaborator or with one of the clinical coordinators in the Oxford coordinating centre.

All randomised patients, irrespective of whether or not they continue to take the study treatment, will be encouraged to attend their routine Follow-up clinic visits. If, however, a randomised patient becomes unwilling or unable to attend the Follow-up clinics, then the clinic nurse is to telephone the patient at the time of each of the scheduled Follow-up visits in order to complete the Follow-up Form. Patients who stop attending clinic follow-up will be asked to return their regular study treatment, but (if appropriate) can then be provided with capsule only (i.e. vitamins or placebo) packs by mail.

Early Recall visits to monitor significant biochemical abnormalities or other problems, and for treatment modification

Biochemical abnormalities requiring action will be reported back to the clinic staff promptly by the coordinating centre, and appropriate arrangements will be made by the coordinating centre with the patient to attend an Early Recall visit. The planned monitoring procedures for significant biochemical abnormalities are summarised below (see Hospital Manual for details):

ALT: ALT >4xULN is to be checked within about 1 week, while ALT >2xULN but <4xULN is to be checked within about 3 weeks. If repeat ALT >4 xULN then study treatment should be stopped temporarily; whereas if >2 but < 4xULN, ALT is to be checked again in about 3 weeks, with study treatment then stopped temporarily if ALT remains >2xULN. After stopping study treatment temporarily, ALT is to be checked again in about 6 weeks and study treatment stopped permanently if still >1.5xU LN (with 3-week Follow-up visits until ALT reverts to normal: i.e. <1.5xULN). If, on the other hand, ALT <1.5xULN then the allocated study treatment can be started again, with a further 2 Early Recall visits at 3-week intervals (at which ALT must remain <2xULN, otherwise study treatment is to be stopped permanently).

CK: Symptoms of myopathy (i.e. new unexplained muscle pain or weakness) accompanied by an otherwise unexplained elevation of CK > 10xULN should result in the study treatment being stopped permanently (with 3-week Follow-up visits until CK reverts to normal: i.e <3xULN). CK >4xULN but <10xULN that cannot be explained (i.e. by some trauma, intramuscular injection, heavy exercise, recent myocardial infarction, etc) is to be checked within about 1 week and, if repeat CK >4xULN then study treatment should be stopped temporarily. CK is to be checked again in about 6 weeks and study treatment stopped permanently if still >3xULN. If, on the other hand, CK <3xULN then the allocated study treatment can be started again, with a further 2 Early Recall visits at 3-week intervals (at which CK must remain <3xULN, otherwise study treatment is to be stopped permanently).

In addition to monitoring ALT and CK as above, the following events are considered sufficient reason to discontinue the simvastatin component of the study treatment permanently:

N.B. Patients who stop study tablets (simvastatin or placebo) permanently may continue study capsules (vitamins or placebo), in which case they will be provided capsule-only packs.

Immediate reporting of any serious adverse experiences believed to be due to study treatment

To fulfil regulatory authority requirements, serious adverse experiences believed with a reasonable probability to be due to study treatment should be reported immediately by telephoning the 24-hour service, where a few brief details will be recorded. For the purposes of this study, the only adverse experiences that need to be reported in this way are those that are both:

  1. serious (i.e. 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), and
  2. believed with a reasonable probability to be due to study treatment.

It is not required to report in this way those serious adverse events that are not thought to be due to study treatment. Such events are, however, to be routinely recorded on the Follow-up Forms for central analysis for the Data Monitoring Committee (see Section 2.5).


Assessment of effects of treatment on lipid profile and vitamin levels

To assess the overall effects of study treatment on the detailed lipid profile and vitamin levels in the different treatment groups in this placebo-controlled study, it suffices to assay these in a random sample of a few per cent of the patients during the study. So, about 5% of the blood samples will be selected by the coordinating centre each year for extensive analysis and storage in liquid nitrogen. (HbA1c, and creatinine will also be analysed at the end of the study among a random sample of about 1000 diabetics.)

Confirmation of non-fatal events

The coordinating centre will seek confirmation and additional information (including, if necessary, any relevant hospital discharge records) from the patient's general practitioner about each suspected MI, stroke, coronary angioplasty, vascular surgery, cancer, and other relevant hospitalisation or serious adverse experience recorded on the Follow-up Forms. (N.B. In response to results emerging from this and other relevant studies, during and after the scheduled follow-up period, further details may also be sought for other events.) This will allow central review of relevant events blind to treatment allocation. The diagnosis of MI requires either (i) the presence of two or more of: (a) typical ischaemic chest pain, pulmonary oedema, syncope or shock; (b) development of pathological Q-waves and/or appearance or disappearance of localised ST-elevation followed by T-wave inversion in two or more of twelve standard electrocardiograph leads; and (c) increase in concentration of serum enzymes consistent with MI (e.g. CK >2xULN); or (ii) necropsy findings of MI of an age corresponding to the time of onset of symptoms 62 ("Silent" MIs are not to be included.) For any strokes reported, information will be sought particularly on aetiology (i.e. haemorrhagic or not) and severity, and for cancers, information on primary site will be sought.

Follow-up of deaths and of non-fatal cancers

The Oxford coordinating centre will seek, for all randomised patients, the certified causes of any deaths and details of any registered non-fatal cancers from the Office of Population Censuses and Surveys (OPCS) Central Registry. Notification of deaths and cancers by OPCS is independent of whether patients are still complying with study medication, and of whether they are still attending the clinic for regular follow-up (so long as they remain within the United Kingdom). Consequently, it ensures unbiased cause-specific mortality and site-specific cancer incidence data for all patients, both during the treatment period and for the indefinite future thereafter. Causes of death will have been coded by OPCS according to the Ninth International Classification of Diseases (ICD). Date of death and the name of the certifying doctor are provided so that, where necessary, further details can be sought from hospital case records and/or general practitioner records.

HPS * Front Cover * Contents * Section 1 * Section 2 * Section 3 * Appendix * References * Back Cover