MRC/BHF Heart Protection Study

Questions and Answers about the Heart Protection Study

This information is also available to download HERE as an MS-Word document.

Q What is the Heart Protection Study (HPS)?
A It is the world's largest ever trial of cholesterol-lowering drugs and of antioxidant vitamins, and the first cholesterol-lowering trial to include a substantial number of women, elderly people and those with diabetes and with below-average cholesterol.
Q Who carried out the study?
A The Clinical Trial Service Unit (CTSU) at Oxford University designed, coordinated and analysed the study, which involved 69 hospitals throughout the UK. CTSU's work chiefly involves studies of the causes and treatment of major diseases such as heart attack, stroke and cancer.
Q Why was it undertaken?
A Throughout the whole range, blood cholesterol levels are an important cause of coronary heart disease (CHD). Prolonged lower blood cholesterol levels are associated with lower risks of CHD. Cholesterol-lowering therapy may therefore be worthwhile for individuals at high risk of coronary heart disease events irrespective of their cholesterol levels. Observational studies also suggest that increased dietary intake of antioxidant vitamins may be associated with lower risks of CHD. Heart disease is Britain's biggest killer, the biggest killer throughout the developed world, and an increasing killer in the developing world. Even a small reduction in the numbers who suffer from it each year could save far more lives than a much larger reduction in the numbers who suffer from rare diseases.
Q What were the study objectives?
A Primary objectives: to assess in a wide range of people at increased risk of CHD, the effects of:
  • prolonged cholesterol-lowering with a statin on total and cause specific mortality; and
  • supplementation with antioxidant vitamins E and C and beta-carotene on total CHD and fatal CHD.
  Secondary objectives: to assess:
  • the effects of cholesterol-lowering with a statin on deaths from coronary disease, from other vascular causes, and from various non-vascular causes, including cancer.
  • the effects of cholesterol-lowering with a statin, and of antioxidant vitamin supplementation, on total CHD in the first 2 years and in the later years of treatment (to see if the effect increases with time); the effects on cause-specific mortality during the treatment period (and in the longer term); and the effects on total stroke and presumed ischaemic stroke during the treatment period.
  • the effects on total CHD and on major vascular events in lots of different sub-groups of patient: for example, those in different prior disease categories, men and women, young and old, and those with different blood cholesterol levels at presentation.
Q What type of study was it?
A A randomised double-blind clinical trial; i.e. one in which volunteers randomly receive either the active study treatment or a placebo (dummy tablet or capsule), and in which neither volunteers nor doctors know who is receiving active study treatment and who is taking a placebo.
Q What has this study told us that we did not know before?
A Cholesterol-lowering with statins has now been shown to be effective for a much wider range of people at increased risk of vascular disease because of their past medical history:
  • Not just those who've had a heart attack or have angina but also those who've had a stroke or have peripheral arterial disease or diabetes mellitus;
  • Women as well as men, and those aged over 70 as well as middle-aged people;
  • Not just those considered to have elevated cholesterol levels but also those whose cholesterol levels might previously have been considered low. There is no "threshold" apparent within the range seen in Western populations for which lower cholesterol is not associated with lower risk of vascular disease.
  Cholesterol-lowering with statins reduces the risk not just of heart attacks but also of strokes, coronary surgery, other vascular procedures, and hospitalisations for worsening angina.
Q Why did you study people who already had vascular disease or diabetes?
A Because such people are at particularly high risk of heart attacks and strokes, and so have the most to gain from a reduction in their risk. They are also easily identified from existing medical records, so it should be straightforward for doctors to use the findings for the care of their patients without the need for complicated screening procedures. The observation that benefit is found irrespective of the patient's cholesterol level means that doctors can make the decision to treat based on the patient's medical history without having to wait for the results of a blood cholesterol measurement. This simplifies the management of these high-risk patients considerably, which should help to ensure that they are treated appropriately.
Q Which people should consider statins who may not have considered them before?
A People with a history of heart attack or angina who are aged over 70, and those who have blood total cholesterol levels below 5.0mmol/l or LDL cholesterol levels below 3.0mmol/l, should now consider statin treatment. As should all those with a history of stroke, other occlusive vascular diseases, or diabetes, regardless of their age, sex or cholesterol level.
Q Now that you have the results, what is your advice to people suffering any of the conditions that statins have been shown to benefit?
A People with a history of heart attack, angina, stroke or peripheral artery disease, as well as those with diabetes, should discuss these findings with their own doctor in order to decide whether cholesterol-lowering with a statin would be appropriate for them.
Q What would be the effect on the risk of a heart attack or stroke if a person is already receiving other treatments to lower risk?
A The benefits of cholesterol-lowering with statins are additional to those of other effective treatments for vascular disease (such as aspirin and blood-pressure lowering drugs).
Q Should every person now having vascular surgery consider statins? Does this include people who, for example, have surgery for vascular injury, as opposed to disease?
A All patients who have had surgery (or other procedures) on coronary or non-coronary arteries to bypass or remove narrowings due to atherosclerosis should now be considered for cholesterol-lowering with statins, regardless of their cholesterol levels.
Q Your study showed that people with diabetes benefit, even if they have not had a CHD event. Does this mean that everyone with diabetes, no matter how healthy, should consider statins?
A Provided a person with diabetes is at high enough risk of vascular disease (perhaps due to their age or other risk factors) for a reduction of about one-third in their risk to be worthwhile, then statin therapy may well be worth considering.
Q How many people took part?
A 20,536 finally, but this involved postal invitations to 131,000 and screening 63,603, of whom 32,145 agreed to go into the 2-month run in period prior to study entry.
Q How was the study designed to assess the various combinations of treatment?
A It is known as a factorial (2 x 2) design.
  • 5,000 were allocated active statin and active vitamins
  • 5,000 were allocated active statin and placebo vitamins
  • 5,000 were allocated placebo statin and active vitamins
  • 5,000 were allocated placebo statin and placebo vitamins
  Assessment of cholesterol-lowering involves comparisons of the 10,000 allocated active statin versus the 10,000 allocated placebo statin. Likewise, the assessment of antioxidant vitamin supplementation involves comparisons of the 10,000 allocated active vitamins versus the 10,000 allocated placebo vitamins.
Q Was it difficult to recruit volunteers?
A We needed to invite 2 to get 1 to turn up for screening. About half of those screened were initially both eligible and willing and started on the 2 month Run-in phase. Of the half who did not enter, one third would have been eligible but refused, one third would have had difficulty attending clinics regularly, and one third were not eligible. Of those who started the Run-in about 2/3 were finally recruited. So about 16% of those initially approached by letter entered the study. This compares favourably with other studies.
Q How many men and how many women took part and what age were they?
A 15,454 men and 5,082 women aged between 40 and 80 at the time of screening.
Q Why were there three times as many men as women?
A Men suffer from heart disease at a younger age than women do, and so there were more men within the study age range available to approach. But it was also more difficult to recruit women - for each 100 invitations sent to men about 17 were willing and eligible to join. For each 100 invitations sent to women only about 9 agreed. We do not know why there was this difference. Nevertheless, this is still the largest study to look at cholesterol-lowering in women, because we made special efforts to recruit women. In fact, it is the first to include a substantial number of women. Up to now the effects of cholesterol-lowering in women have been extrapolated from evidence in men.
Q Evidence in women was sketchy before. Now it looks as if women benefit in the same way as men. How important is this finding for women?
A As this is the biggest study of cholesterol-lowering in women these results are definitive. Cholesterol-lowering has now been shown to reduce the risk of vascular disease to about the same extent in women as in men. Women tend to develop vascular disease at older ages than men, so the evidence of benefit in this study among people aged over 70 is also of great relevance to improving the health of women.
Q What other categories of volunteers were specially needed?
A Groups who were at particularly high risk of heart disease for whom there had been too little evidence, including:
  • People with diabetes - they are at high risk of developing heart disease.
  • People over 70 - a group often overlooked by previous smaller studies, and in which statin use is controversial.
  • People with non-coronary vascular disease - for example, those that had suffered strokes, mini-strokes or other circulatory problems.
  • People with pre-existing vascular disease or diabetes who had average or below-average cholesterol levels (since it had been suggested that there might be a "threshold" below which lowering cholesterol would not produce worthwhile benefits).
Q Who was eligible to enter the trial?
A Anyone between the ages of 40 and 80 who was considered to be at substantial risk of CHD within 5 years because of evidence of vascular disease anywhere in the body, or previously diagnosed with diabetes. This meant:
  • any evidence of CHD (heart attack, angina, previous coronary revascularisation).
  • any other vascular disease (other arterial revascularisation, stroke or mini-stroke, or symptoms suggestive of blockages in the leg arteries).
  • any history of diabetes (either type 1 - early onset insulin dependent diabetes; or type 2 - late onset non-insulin dependent).
Q What was the breakdown in participants?
A There was overlap between the groups (i.e. some people had more than one condition putting them at increased risk):
  • history of heart attack - 8,510
  • other history of CHD without heart attack (e.g. angina, heart bypass surgery or coronary angioplasty) - 4,876
  • history of a stroke, mini-stroke or surgery to the neck arteries - 3,280
  • disease of other arteries - 6,748
  • diabetes mellitus - 5,963
  • treated hypertension (high blood pressure) - 8,457
  Other categories:
  • below average cholesterol at baseline (i.e. LDL cholesterol under 3.0 mmol/l: this would be approx. 120mg/dl in US measurements) - 6,793
  • total cholesterol less than 5.0 mmol/l (approx. 200mg/dl in US measurements) - 4,072
  • age 65 and above - 10,697
  • age 65 to 69 - 4,891
  • age 70 and above - 5,806
Q What criteria excluded participation in the trial?
A The main exclusion criterion was a history of any other severe disease that might limit compliance or the ability to attend clinic visits regularly over 5 years, or that might cause death within the next few years. This included severe heart failure, severely disabling stroke, severe chronic airway disease or a history of cancer (other than non-melanoma skin cancer). Because of potential side-effects and drug interactions with statins, we also excluded volunteers with severe liver or kidney disease, muscle disease or any condition likely to lead to organ transplantation. We also excluded people if they had had a heart attack, stroke or had been in hospital for angina in the last 6 months, although they were eligible for recruitment later.
Q How many vascular events have these findings the potential to prevent?
A About 70-100 fewer people having heart attacks, strokes or revascularisation operations for every 1,000 patients treated for 5 years. Or more relevant, given the very much wider range of people now shown to benefit, 70-100,000 fewer people having such major vascular events in every million extra that are treated.
Q How many deaths do these findings have the potential to prevent?
A About 20-30 fewer deaths per 1,000 - or 20-30,000 fewer per million - treated for 5 years.
Q Are these results definitive?
A Absolutely: the large numbers in each separate group of interest make these findings definitive.
Q You have looked at the results in a range of subgroups - but the CTSU often warns of the risks of subgroup analysis. So how confident are you of your results in subgroups?
A This study was deliberately designed to have large enough number of patients in a range of different pre-specified categories to provide reliable direct evidence for each group for which there had been uncertainty. So, for example, the group aged over 70 is larger on its own than the total number of people of all ages in most previous statin trials.
Q For how many people are these results relevant?
A It is estimated that up to 25 million people worldwide are currently being treated with a statin. World Health Organisation statistics indicate that there are about 200 million people worldwide with CHD, stroke, other occlusive vascular disease or diabetes mellitus [see Global Statistics on for regional numbers]. Consequently, the present findings are directly relevant to starting statin treatment in some tens of millions of people at increased risk of heart attacks and strokes.
Q Can we afford to act on these findings?
A Can we afford not to? The benefits are large and the costs should fall substantially as statins come off patent during the next few years. Currently, 40mg daily simvastatin (or an equivalent dose of another statin) costs approximately £1 per day in the UK and $4 per day in the US. The patent for lovastatin (Mevacor) has already expired in the US, and the patent for simvastatin (Zocor) expires in most of Europe (including the UK) in mid-2003 and in the US in 2006.
Q CHD is increasing in the developing world - how can developing countries possibly afford this treatment?
A As the patents expire, cheaper "generic" statins will soon be available. So, as with the generic antihypertensive drugs already available in developing countries, the costs should become manageable for very many more people around the world.
Q Will the results be applicable to any statin?
A The consistency of these results with those from previous statin trials, as well as the enormous amount of evidence available about cholesterol-lowering before the statins were available, make it highly likely that any benefits of cholesterol-lowering are applicable to all statins that lower cholesterol by a similar amount. Whether or not the safety data can be extrapolated to other statins is a more difficult issue.
Q Did these results surprise you?
A It's not surprising that lowering cholesterol lowers the risk of heart attacks in some circumstances, but it is surprising that lowering cholesterol is beneficial in such a wide range of high-risk individuals - including even those with cholesterol levels not considered to be high by current guidelines.
Q Which, among the findings, surprised you most?
A In observational epidemiology studies, blood cholesterol levels are very strongly associated with the risk of heart attack but not with the risk of stroke. So, the definite reduction in stroke produced by statin therapy is the most surprising finding (even though there was some evidence for an effect in previous statin trials).
Q Were there any disappointing findings from this study?
A Not for cholesterol-lowering with statins - those results are wonderful news for people at high-risk of heart attacks or strokes. It is, however, disappointing that the antioxidant vitamins did not produce any benefit in this high-risk population.
Q How do these findings for statins compare with other studies?
A In the main they are consistent with previous trials. But, because this trial was so much bigger and included a much wider range of high-risk patients, it has been able to demonstrate benefit with statin therapy for many more groups of patients than had previously been thought to benefit.
Q Do these results change or modify findings from other studies? If so, how?
A Yes, they refute entirely the suggestion that there might be a threshold of LDL cholesterol at about 3.0mmol/l (120mg/dl) below which lowering cholesterol does not produce lower risk. The present results indicate that guidelines to lower cholesterol levels to "target" levels of about 3.0mmol/l for LDL cholesterol, or 5.0mmol/l for total cholesterol, are no longer appropriate.
Q Is there a threshold below which cholesterol should not be allowed to fall?
A Cholesterol is needed by the body, so there must be a threshold. But, the present findings indicate that it is much lower than the levels typically seen in Western populations. Studies in China find very much lower cholesterol levels than we are used to seeing, and very much lower heart attack rates.
Q Why was there a smaller effect on death than on vascular events?
A About half of the patients who died in the study died from vascular causes (which might be expected to be reduced by lowering cholesterol) and about half from non-vascular causes (which, chiefly, would not be expected to be reduced). The effects of cholesterol-lowering on deaths from heart attacks, strokes and other vascular causes are not dissimilar to the effects on non-fatal vascular events, with no effect observed on deaths from other causes.
Q Did every participant take their allocated daily simvastatin or matching placebo tablets throughout the scheduled study treatment period?
A No. On average during the study, about one-sixth of participants allocated placebo were prescribed a non-study statin by their own doctors and about one-sixth of those allocated study simvastatin stopped taking statin. So, instead of 100% of those allocated simvastatin taking it throughout the study and 0% of those allocated placebo taking a statin, the actual difference between these groups in statin use was only about two-thirds as large.
Q How does this non-compliance with the allocated study treatment affect the assessment of 40mg daily simvastatin?
A To avoid bias in the assessment of treatment, the analysis of a randomised trial like this involves "intention-to-treat" comparisons between all those allocated simvastatin and all those allocated placebo. But, after making appropriate allowance for the average compliance in this study of about two-thirds, it can be estimated that the average reduction in LDL cholesterol of about 1.0mmol/l (40mg/dl) seen in an intention-to-treat analysis represents a reduction of about 1.5mmol/l (i.e. 1.0 x 3/2) with actual use of 40 mg daily simvastatin. Similarly, for the effects on vascular disease risk, the reductions of about one-quarter in the intention-to-treat analyses with two-thirds compliance would be expected to translate into reductions in vascular disease risk of about one-third with full compliance to 40 mg daily simvastatin.
Q Patients prescribed medicines often stop taking them after a few years, would this matter for statins or will people still obtain benefits?
A Statins only lower cholesterol while they are being taken and the benefits start within a year of beginning to take them. It is therefore extremely important that they are taken regularly over many years, and are not stopped without good reason. The good thing is that the benefits of statins get bigger as they are taken for longer.
Q What further studies need to be done on cholesterol-lowering?
A Some high-risk patient groups have been largely excluded from previous cholesterol-lowering trials. In particular, there is a need for some large-scale definitive studies among patients with kidney disease, which is a group at increased risk of vascular disease for reasons that are poorly understood.
Q Are you doing further studies in this area?
A Yes, we are currently conducting a trial in 12,000 heart attack sufferers (SEARCH) to find out whether even bigger reductions in cholesterol produce even bigger reductions in risk. And, we are also now planning a study of cholesterol-lowering in patients with impaired kidney function who have not already developed evidence of coronary disease.
Q Do these results tell us anything about the optimum dosage of statins, and does it matter which statin is prescribed?
A The present study used 40mg daily simvastatin, which was very effective at lowering cholesterol levels and the risk of vascular disease, while avoiding much in the way of side-effects. Other statin regimens that produce similar cholesterol reductions without side-effects seem likely to be about as effective. Newer trials (such as our SEARCH trial with simvastatin and the TNT trial with atorvastatin) are studying the effects of bigger cholesterol reductions with higher statin doses, but these may be associated with a somewhat greater incidence of side-effects.
Q In relation to the people at inherited risk of high cholesterol - the 1 in 500 with familial hypercholesterolaemia (FH) - should very young people, even children with this condition, be considered for cholesterol-lowering therapy?
A This study did not directly address the question of cholesterol-lowering in people aged under 40. But, it does indicate that cholesterol-lowering with statin therapy reduces vascular disease risk by at least one-third in a very wide range of individuals. So, if such a reduction would be worthwhile, then it would be appropriate to consider statin therapy in groups beyond those studied directly in the trial (including younger individuals with familial hypercholesterolaemia).
Q How much has the study cost?
A About £21 million (GBP) over eight years - nearly $32 million (US).
Q Who paid for it?
A Funding was from 4 sources - the UK's Medical Research Council (MRC), the UK's British Heart Foundation (BHF) and the international pharmaceutical companies Merck & Co Inc [manufacturer of the statin] and Roche Vitamins Ltd [manufacturer of the vitamins]. The funding was provided as grants to Oxford University, so that the pharmaceutical sponsors had no say in how the money was spent, in the day-to-day running of the study, the analysis of the data, or the way the results are presented, published or publicised.
Q Is the study independent of the sponsors?
A Yes. The idea for this study came from the principal investigators in CTSU, and it was designed, has been run, and is being analysed and interpreted by them, entirely independently of all the sources of funding. Indeed, quite unusually, the sponsors will not even have direct access to the full data file (except to audit the quality of the data) so that all analyses are conducted free from any potential conflicts of interest. Data will, of course, be made available to government regulatory authorities so that they can confirm the study analyses, but this will be done directly between these authorities and the investigators.
Q What other steps are taken to ensure the independence of the research?
A A data monitoring committee, which does not include anyone involved in the trial, has acted as watchdog, examining interim analyses, and responding to any concerns.
Q When did the study start?
A The first patients were recruited to a pilot study in 1987. Planning and fund-seeking for the main study started in 1990. The first patient was recruited in May 1994. The 20,000th volunteer was recruited on 8 April 1997 and recruitment finished that year.
Q How many hospitals took part in the study?
A 69 UK hospital-based clinics [see Centres and Collaborators on for locations and names of collaborating hospitals]
Q How many doctors took part?
A About 85: 51 hospitals had 1 doctor involved, but other hospitals had 2 or 3.
Q What specialities did these doctors represent, and were there any general practitioners (i.e. family doctors)?
A All the collaborating doctors were consultants and all were hospital-based. There were nearly 30 cardiologists (many of whom were also general physicians), 18 lipidologists or chemical pathologists, 12 diabetologists (who were mostly also general physicians), 21 other general physicians, 3 neurologists and 1 vascular surgeon. But even though general practitioners were not directly involved, about 10,000 general/family practices helped by providing further information about medical conditions (such as heart attacks and other vascular disease) reported by participating patients during the study.
Q How many nurses took part?
A Towards the end about 70, but over the course of the study there have been almost 200.
Q How many clinic visits did the volunteers make in total?
A There have been 308,000 consultations, of which 286,000 (93%) were face to face - i.e. in clinic (more than 99%) or in hospital or at home. The other 7% were telephone contacts.
Q How many visits did each volunteer normally need to make?
A It varied, but anything up to 20, with most volunteers having 12-15 visits.
Q How many blood samples were collected and analysed?
A Blood was taken for analysis during a total of 258,000 volunteer consultations.
Q How many forms did you collect?
A 292,000 forms on paper, and about 17,000 electronically at the final follow-up visit.
Q How was such a huge trial organised and run from one unit?
A Teamwork and streamlining. About 20 computing, administrative and clerical staff at the CTSU in Oxford coordinated all 69 clinics. Potentially suitable participants were identified from local hospital databases. Letters were sent to all those that might be eligible, in the name of their local hospital doctor. Responses were either returned to the CTSU by post or by using a central Freefone number manned by CTSU staff. The local hospital doctors employed senior nurses to set up and run HPS clinics in their hospitals. The nurses liaised closely with the CTSU and were sent lists each week of the people who had been invited and when they were expected to attend. All appointments were managed through the coordinating centre computer, with participants and staff having access to the system via the 24-hour Freefone service. So, at any time during the study, the coordinating office was aware of the status of each patient in each clinic in the UK. All data and blood collected by the clinic nurses were forwarded immediately by courier or mail to the CTSU, and all blood analyses were done by the coordinating centre's laboratory staff.
  Volunteers were seen initially by a nurse for an interview of up to an hour. If eligible and willing to participate, a blood sample was taken and they were given a treatment pack and an appointment to return in two months. If participants did attend for the second visit and were still eligible and willing, they were then randomised into the study with the agreement of their own doctors. The nurse telephoned the central randomisation service on the Freefone number and was told to issue a particular drug pack to the patient. The treatment combination in that pack would be the appropriate one for the treatment group to which that individual had been allocated at random.
Q This trial called for a great degree of co-operation and commitment from volunteers - what did CTSU offer in return?
A It would not have been possible to undertake this trial without our volunteers. We are enormously in their debt and immensely grateful to them all. We were very aware that taking part demanded commitment. We were determined that the participants should be kept fully informed of anything relevant to the study (with the agreement of their own doctors). We provided regular newsletters for every volunteer, with information on the aims and progress of the trial, new findings from similar trials, articles about the experience of participants and tips on healthy living.
  In addition, it was important for advice to be available for medical staff and volunteers who had any questions or concerns about the study. So, the clinicians at CTSU worked a rota to provide a 24-hour on-call service. The preliminary results of this trial, which were made public on 13 November 2001, were posted to all volunteers and their general practitioners at the same time as they were announced by the investigators at the American Heart Association meeting in Los Angeles. Full details are also available on a special website set up by the CTSU at:
Q How did you cope with volunteers who became ill on the trial (e.g. had a heart attack)?
A Throughout the trial, the volunteers' own doctors remained responsible for their patients' care. If a participant had a heart attack their management was up to the local doctor. If the doctor felt that cholesterol-lowering treatment was indicated they were free to prescribe whatever they thought was most appropriate for that particular patient. Until early 1998, such patients would have stopped their study statin or placebo tablets. After that date, when it had become clear that higher doses of statins were well tolerated and apparently safe, prescribed statin could be added to study treatment if the dose of the non-study statin did not exceed the equivalent of about 40mg daily simvastatin (the study statin).
Q Would the participant be "unblinded" so the doctor knew what drug the patient was taking?
A If a doctor specifically needed to be unblinded that would have been done, but normally they were asked to make a decision about cholesterol-lowering treatment based on their usual criteria. As the trial has progressed, the proportion of participants prescribed non-study statin has gradually increased. By final follow-up in 2001, about a fifth of volunteers were on additional statin, over half of whom were also taking the study statin or placebo.
Q Did you have to "unblind" any volunteers during the trial because of major problems?
A Remarkably few. We were obliged to report to the regulatory agencies all "serious adverse events" thought with reasonable probability to be due to study treatment. There were only 16 such reports among the 20,536 randomised volunteers during an average of 5-6 years of treatment, all of whom were unblinded. However, in the light of the unblinding and other information, some of these problems were later not thought to be due to study treatment.
Q What was the drop out rate from the trial?
A Relatively low. On average during the trial, about 80% of participants took their allocated study statin or placebo tablets regularly, and 85% took their vitamins or placebo regularly. Because the analysis of results will be done on an "intention-to-treat" basis, everyone who was randomised is counted even if they never took the study treatment. If people were unwilling to continue the study treatments they were still encouraged to continue attending the clinics or, at least, to keep in phone contact. Over 95% were being actively followed in this way, with the remainder followed by contact with their GP.
Q How did you decide which statin to use?
A Simvastatin (Zocor) was the first statin to become available in the UK. CTSU had already run a pilot study among over 600 Oxford volunteers looking at its safety and efficacy at lowering cholesterol. Merck & Co Inc, the manufacturers, were prepared to help fund a large-scale trial jointly with other funders (UK Medical Research Council, UK British Heart Foundation, and Roche Vitamins Ltd which manufactures the vitamins studied).
Q How did you decide what dosage to use?
A Based on our pilot study, which randomised about 200 volunteers to 40mg of simvastatin daily, 200 to 20mg daily and 200 to placebo, the 40mg dose of simvastatin produced somewhat greater cholesterol reductions than 20mg, without any obvious hazards or safety concerns over the first 3 years. Given the continuous relationship between lower cholesterol and lower CHD risk in observational studies, it was felt that the maximum dose then considered safe and available should be used.
Q What is the normal statin dosage range in treatment outside of this trial?
A For simvastatin, which was the statin studied in HPS, the most commonly used doses are 10mg and 20mg daily. Different brands vary slightly in their potency. But the other statins would have similar cholesterol-lowering potency when prescribed at their most common dosage.
Q What percentage of people who could benefit from statins actually gets them?
A Data are always a little out of date but treatment rates are low. Recent sources report the following:
  • Euroaspire 2 (Lancet 2001, Vol 357, 995-1001) collected data in 1999 and 2000 on 3,000 CHD patients in hospitals in 9 European countries, excluding the UK. As they were patients being treated in cardiology centres, the figures may not reflect the general situation (see below). It found that 60% had cholesterol over 5.0mmol/l, with a quarter with cholesterol over 6.0mmol/l. Two-thirds of all people with CHD were on cholesterol-lowering therapy, but only a half reached a target of 5mmol/l or less.
  • In the UK (BMJ 2001; 322:1463), 24,000 patients with CHD from 550 general practices were surveyed in 1997 and 1998. Half the women and one third of the men did not even have their cholesterol measurement documented. Only 18% of men and 13% of women with CHD were on statins.
  • CTSU's own more recent data collected as part of another study shows that 30% of heart attack survivors (for whom previous evidence was strongest) are not on a statin, and 75% of these have cholesterol levels of over 5mmol/l. Of the ones on a statin, a quarter have not fallen below 5mmol/l.
  • In the USA (Circulation 2001; 103: 38-44), among patients in 1998-1999 with a history of heart attack - the strongest indication for a statin - less than a third were discharged on a lipid-lowering drug.
  So, there is widespread evidence of massive under-treatment even among those groups where the evidence of benefit is most clear. There is even less use in other high-risk groups where previous evidence is less clear (such as those without a history of heart disease, the elderly, or those with average or below-average cholesterol levels).
Q How did you decide what analyses to undertake at the start, and have extra analyses been done as a result of findings from other trials that have reported in the meantime?
A At the beginning of the trial, the major concern was the safety of cholesterol-lowering, and its effects on total mortality and other specific causes of death and on heart attacks. As a result of reassuring results from other statin trials many people are less concerned about safety issues, but they remain important, particularly as statins are starting to be used more and more widely. Because of suggestive evidence from other trials, we became very interested in assessing the effects of cholesterol-lowering on stroke, as well as on heart attack and other vascular events, in the various predefined subgroups (such as the elderly, women and people with diabetes, previous strokes or other vascular disease). For the antioxidant vitamins, the main hope was that there would be an effect on coronary events.
Q Why did you include people who already had "low" LDL cholesterol, and was there any risk of doing this (e.g. some studies have controversially pointed to links between low cholesterol and cancer)?
A In observational studies the association between cholesterol and risk of CHD seems to be continuous, without any threshold below which having lower cholesterol is not associated with lower risk. It therefore seemed logical to include people across the whole range of cholesterol levels (including those with average and below-average levels) if those people were otherwise at increased risk of CHD. Only in this way would it be possible to see whether there would be benefit from lowering cholesterol. There have been concerns about safety with cholesterol-lowering, and this has been monitored during the study by the independent data monitoring committee. Previous concerns about cancer illustrate why cancer incidence during the Heart Protection Study is an important endpoint.
Q Has this study finally proved that low cholesterol does not cause or is not associated with cancer?
A There was no evidence in this large trial that cholesterol-lowering treatment produced any increase in the incidence of all cancers, or of cancers of particular sites (such as gastrointestinal cancers) that, it had been suggested previously, might be linked to cholesterol-lowering.
Q There have been reports that low cholesterol may increase mortality in people over 70. Did this concern you?
A These reports illustrate the importance of conducting randomised trials (such as HPS) that reliably study the effects of lowering cholesterol in substantial numbers of older people. It is only with such large-scale randomised evidence that the balance of benefits and any risks can be reliably assessed. HPS has now shown that cholesterol-lowering therapy is beneficial in the elderly.
Q How do you ethically justify having denied some patients statins (in this trial) when it is already well established that statins lower LDL cholesterol?
A Nobody who was thought by their own doctor to need a statin was denied it. But, there are many questions about just how widely statins should be used. At entry to the study, the lipid profile (i.e. total cholesterol, HDL, LDL and triglyceride measurement) of each participant who entered the initial run-in phase was sent to their family doctor (i.e. general practitioner). The family doctor was also sent a form to return if he or she felt that their patient was likely, immediately or in the future, to need to be prescribed statin treatment - in which case that volunteer was not randomised. During the study, the volunteers' family doctors were free to monitor cholesterol levels if they considered this to be indicated. Non-study cholesterol-lowering treatment could be added by the managing doctor at any time.
  We explained to participants at the start of the study that it was already known that lowering cholesterol reduced the risk of heart attacks, but that most people among the range of volunteers recruited were not then receiving any kind of cholesterol-lowering treatment. At that time (between 1994 and 1997) there remained major concerns among many doctors about the safety of cholesterol-lowering, and most thought that there was no need to lower cholesterol in people with average or below-average levels. Subsequently during the study, participants and their family doctors were reminded that non-study cholesterol-lowering therapy (including statins) should be started if, perhaps in the light of emerging evidence from other studies or changes in a participant's condition, it was thought to have become indicated.
Q Your study did not include people under 40 - but should people who are under 40 with risk factors (e.g. people with diabetes) be considered for cholesterol-lowering therapy?
A Patients aged below 40 were not included because they are not generally at high risk of vascular events. But, if a younger patient was at sufficiently high risk of coronary disease or stroke for a reduction of about one-third in that risk to be worthwhile then statin therapy should be considered.
Q Are there any people who should not take statins?
A The data sheet warns against the use of statins in pregnant women and in those with active liver disease.
Q Statins have been associated with muscle problems. What precautions did you take?
A The known rare side effect of myopathy (muscle problems) due to statins dictated some of our trial procedures. People were excluded at the start if they had a history of inflammatory muscle disease or if the blood test for the muscle enzyme creatine kinase (CK) done at the first visit showed a value 3 times the upper limit of normal. All participants were warned at the screening interview about the possibility of muscle pain or weakness, and this was also stated explicitly in the patient information leaflet. Nurses advised volunteers that if they experienced unusual or unexplained muscle pain or weakness they should telephone the study nurse or the 24 hour Freefone number where a doctor was always available to talk to any such volunteer. If muscle pain was thought to be significant, or the doctor considered it prudent, an extra visit was arranged and a blood test done to check the muscle enzyme levels. At all routine visits, nurses asked participants to report any new or unexplained muscle pain. If this was reported a blood sample would be used to check the muscle enzyme CK levels. This is a reliable and specific test for muscle damage.
Q Did you see any muscle problems during the trial, in particular rhabdomyolysis? Is your report reassuring on this aspect?
A Although muscle pain was reported by the participants, this happened about as commonly among those allocated the active simvastatin as among those allocated the placebo tablets. Despite 20,536 randomised patients having been followed for an average of five years, blood tests among people reporting muscle symptoms (as well as among those who added a non-study statin to their study drugs) found only 11 simvastatin-allocated patients and 6 placebo-allocated patients with a rise in the muscle enzyme creatine kinase (CK) to more than 10 times the upper limit of normal (i.e greater than 2,500 IU/l). Of these, 14 met the definition for "myopathy" (i.e. muscle symptoms associated with such CK elevations) of whom 10 were in the simvastatin group and 4 in the placebo group. Eight met the definition for rhabdomyolysis (i.e. CK greater than 10,000 IU/l), 5 in the simvastatin group and 3 in the placebo group, but all recovered from it.
Q If results are reassuring about rhabdomyolysis, why was a particular statin (cerivastatin [Lipobay]) recently withdrawn because of deaths from rhabdomyolysis?
A Different drugs and different doses of drugs may well have different toxicity. The present findings show that 40mg daily simvastatin (Zocor) is very well tolerated, but higher doses have been associated with a small increase in the risk of muscle problems.
Q How can you be sure that the huge amounts of data in this study are correct, and what checks did you make?
A Every time a participant was seen in the study clinic (or followed-up in any other way), they were encouraged to report all medical events that had happened to them (even if these events might not have been thought relevant to the study). Further information was then sought from general practitioners and other medical records by the coordinating centre for all such reports of events that might possibly have been study outcomes, (e.g. heart attacks or strokes). National registries of deaths and of cancers provided further information about relevant outcomes. (A survey of the family doctors of a random sample of 1000 participants found that very few relevant outcomes had been missed.) The available information on each possible study outcome was reviewed "blind" to the allocated study treatment by a doctor in the coordinating centre, and the reported event was coded as either confirmed or refuted. The main analyses were checked by running separate analysis programs produced by an independent statistician within the coordinating centre.
Q Were there any difficulties in deciding on causes of death for those volunteers who died during the study, and how did you resolve them?
A Deaths were reported to the coordinating centre by participants' families, their general practitioners, study nurses and the national death registries. Information available on each death included a copy of the official death certificate as well as other relevant medical records (including, for example, coroners' autopsy reports). All deaths were reviewed independently by two doctors in the coordinating centre unaware of the study treatment allocation, and any disagreements on the underlying cause of death resolved by discussion (with, if necessary, another doctor).
Q Why did the trial also look at vitamins?
A In the early 1990s there was enormous interest and optimism about the potential of antioxidants to reduce the risk of CHD. A large body of epidemiological data showed that people with higher intakes of antioxidant vitamins in the diet were less likely to suffer heart disease. Small-scale trials had suggested benefit from vitamin supplements but the results were uncertain. There also seemed to be a good theoretical rationale as LDL cholesterol is more likely to be deposited in the arterial wall if it is oxidised, and dosing with oral antioxidants makes it less likely that the LDL cholesterol becomes oxidised when exposed to oxidant stress. Large-scale trials of vitamins alone are often difficult to fund, so adding a vitamin component in a factorial design to another funded comparison is a good way of answering both questions.
Q Why did you choose the vitamins you did choose?
A The antioxidant vitamin of most interest at the time the study was being planned was vitamin E. There was a further scientific rationale that a combination of water soluble (vitamin C) and lipid soluble (vitamin E and beta carotene) antioxidant vitamins may be more efficacious, with added vitamin C also helping in the regeneration of vitamin E in the body. So we were happy to use a combination of antioxidants, and Roche Vitamins Ltd agreed to help fund a study using this antioxidant vitamin combination.
Q What was your reaction to the findings on antioxidant vitamins?
A Disappointment. These vitamins - E, C and beta-carotene - are relatively inexpensive and widely available. But, this study shows that they do not produce any reductions in the risk of heart attacks, strokes or other vascular outcomes (or indeed, of cancers or other major outcomes) in high-risk individuals with pre-existing vascular disease or diabetes.
Q Was there any good news about antioxidant vitamins?
A The results for vitamins did, at least, resolve previous concerns about possible hazards - such as suggestions of increases in cancers with beta-carotene, or strokes due to bleeding with vitamin E.
Q Is it possible the trial closed too early to see benefits from vitamins, and is there scope for future studies?
A Although longer treatment and follow-up might demonstrate benefit with vitamin E, C and beta-carotene in this high-risk population, there was no suggestion of any benefit emerging in the later years of study follow-up. Other large-scale trials are currently assessing the effects of these vitamins in low-risk populations, and there will be continued follow-up of participants in HPS to see whether any effects emerge in the longer term. Other vitamins, such as folic acid for lowering blood levels of homocysteine (which has been linked to increased vascular disease risk), are also now being tested in large-scale trials.
Q The results of previous studies on vitamins have been mixed, but some have shown benefit. How do you explain these findings compared with those studies?
A Observational studies of the association between the consumption of vitamin E, C and beta-carotene and the risk of vascular diseases had previously produced promising findings. But, in such observational studies, the people who consume higher levels of such vitamins may differ from those who do not in other ways (such as by smoking less) that are actually responsible for their lower risk. By allocating vitamins or placebo at random, the present trial assessed unbiasedly the effect of changing only the intake of these vitamins (with everything else kept the same), and so avoided these difficulties of interpretation. It did, however, only study high-risk people with pre-existing disease, many of whom were taking treatments (such as aspirin, ACE inhibitors and beta-blockers) shown previously to prevent heart attacks and strokes.
Q What doses or amounts of antioxidant vitamins were used?
A A mixture of 600mg of vitamin E, 250mg vitamin C and 20mg beta-carotene daily, either alone or in combination with the cholesterol-lowering statin.
Q Can these intakes be achieved through diet, and if so, what foods must be eaten?
A A recommended plant-based diet that contains 5 to 9 servings per day of fruits and vegetables can provide 250mg of vitamin C. Diets recommended by the National Cancer Institute in the US and the US Department of Agriculture have been shown to provide 6-7mg of beta-carotene daily. Vitamin E is more difficult; it is present only in small amounts in food, and the richest sources (such as vegetable oils, nuts and seeds) are usually high in calories.
Q How could you control what volunteers did in terms of taking extra vitamins, given that they are available over the counter?
A Participants were asked to avoid taking high doses of vitamin E, but it was not forbidden. In a large study such as this, it would be extremely unlikely that a few individuals taking non-study vitamins would affect the analyses and there are likely to be similar numbers of such people in each of the treatment groups. No restrictions were put on multivitamin use, but we know the rates of use overall are low and, typically, multivitamin preparations contain less than 10mg vitamin E. Blood tests showed that participants allocated the active vitamins had an approximate doubling of blood levels of vitamin E, an increase of one-third in vitamin C and a quadrupling of beta-carotene levels.
Q Were you concerned about the recent report that antioxidants may interfere with the effects of statins on cholesterol?
A This was an interesting observation of an apparent effect of vitamins on the increase in good HDL cholesterol produced by the combination of statin and niacin (another treatment for lowering LDL cholesterol), but it was based on a fairly small number of individuals. In the very much larger numbers in HPS, no such effect was observed with the vitamins studied on the slight HDL-raising effect of simvastatin on its own. This again illustrates the importance of getting large-scale randomised evidence, and looking at clinical endpoints, rather than lipid measurements as surrogates.
Q So, does this mean advice about "eating our greens" is now out of date?
A No. Just because increased consumption of some isolated components of a "healthy" diet does not reduce risk it does not mean that some other components of such a diet are not protective.
Q Should the promotion of these vitamins for health reasons now stop?
A The present results, along with those from other randomised trials of these vitamins, do not provide any clear evidence of worthwhile benefits on health from dietary supplementation with vitamins E, C and beta-carotene (at least in Western populations, such as the UK, that are already reasonably well nourished).
Q Do you intend to follow all volunteers to see what happens to them longer-term?
A Deaths and cancers among study participants will be followed centrally via national registries so that the longer-term effects of the study treatments can be assessed. The feasibility of prolonged follow-up of other non-fatal outcomes (such as heart attacks and strokes) via questionnaires to participants is currently being investigated.
Q Were volunteers told whether they were on active treatment or placebo?
A We did not tell them routinely, but if they wanted to know they could find out by ringing the Freefone number.
Q Why did you not plan to tell them?
A Some people obviously do want to know and they can easily find out. However, experience tells us that not everyone wants to know. The main reason for not telling people is that it minimises the risk of bias in the collection of long-term follow-up. (Someone's knowledge of which treatment they had may affect what they later report.) These effects are subtle but important. The reasoning is the same for keeping those who collect and code reported events blind to the treatment allocation.
Q What if the volunteer asks his doctor?
A A patient's own doctor can request to be unblinded in the same way that a patient can.
Q What was your reaction to the findings on cholesterol-lowering?
A Excitement, since the findings are immediately relevant to improvements in health for some tens of millions of high-risk people around the world.
Q What lessons are there from the study for those at lower risk of vascular disease, and for the general population?
A People at much lower risk of vascular disease than those included in the study would typically have much less to gain from cholesterol-lowering therapy, so the cost and the inconvenience of drug treatment (including a slight risk of side-effects) might not be considered worthwhile. The finding in this study that cholesterol-lowering reduces risk regardless of the cholesterol level does, however, have implications for the general population. It suggests that lowering cholesterol by changes in diet would be expected to reduce vascular disease risk in Western populations.