J R Soc Med 2004;97:461-464
doi:10.1258/jrsm.97.10.461
© 2004 Royal Society of Medicine
The case for statins: has it really been made?
Andrew Thompson PhD 1
Norman J Temple PhD 2
1 Riehen, Switzerland
2 Athabasca University, Athabasca, Alberta, Canada
Correspondence to: Norman J Temple PhD, Centre for Science, Athabasca
University, Athabasca, Alberta T9S 3A3, Canada E-mail:
normant{at}athabascau.ca
 |
INTRODUCTION
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Statin drugs are a modern success story. They are
the medical
treatment
for coronary disease and the star of the pharmaceutical industry.
Worldwide,
sales of statins are running at about $19 billion a year and
growing
quickly.
1
This success profits not only the pharmaceutical industry
but also all those
whose finances and careers are furthered
by the research and the sales. But to
what extent is it also
a success for the general public? To answer this we
will look
at the major long-term (five to six year) clinical trials of
statins.
We start with the treatment offered to the participants, then
look at
the endpoints that were selected, and continue with
a look at how the results
have been reported. We conclude with
a discussion of the cost-effectiveness of
statins for people
at different levels of risk of coronary heart disease
(CHD).
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THE COMPARISON GROUP: BEST CURRENT TREATMENT OR PLACEBO?
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The control groups in all of the trials have been given placebo
pills. A
more strenuous comparison, that of the ‘best
current prophylactic,
diagnostic, and therapeutic methods,’
was advocated by the World Medical
Association in the Declaration
of
Helsinki.
2 For
statins, this is not another drug but lifestyle
factors. The European
Atherosclerosis Society 1987 guidelines
made dietary management ‘the
sole therapy for the majority
of people with elevated levels [of blood
lipids]’.
3
Furthermore,
‘A dietitian, supported by the patient’s physician,
is
best able to instruct the patient, adapt the diet to energy
needs and food
preferences, and [if the response is inadequate]
to monitor ongoing
compliance.’ A year later the US National
Cholesterol Education
Program
4 stated:
‘Drug therapy is likely to continue for many years, or for a
lifetime. Hence, the decision to add drug therapy to the regimen should be
made only after vigorous efforts at dietary treatment have not proven
sufficient.’
Vigorous efforts are defined as a minimum of six months of intensive
dietary counselling before starting drug therapy. This is to occur in two
steps. Step one involves a total fat intake of less than 30% of calories, less
than 10% of which is saturated fat, and less than 300 mg per day of
cholesterol. If that does not bring the blood cholesterol down to the target
level, then a step two diet is initiated which lowers the intake of saturated
fat and cholesterol still further. ‘Involvement of a dietitian is very
useful, particularly for intensive dietary therapy such as the Step Two
Diet.’4
All of the trials were initiated after the publication of these
guidelines.5–13
What the researchers did instead was to recommend a step one diet, wait a few
weeks—not six months—and then, if the desired levels of blood
cholesterol were not reached, enrol the patients into the study proper.
Why were these guidelines not followed? Certainly the initial cost would be
greater, but from a public point of view it would seem advisable since a
dietary regimen would not only help reduce CHD but could have a beneficial
result on several other diseases and save on the costs of multiple procedures,
not just statin drugs.
One thing that might have happened if all participants had been given
dietary intervention before starting statins is that it would have much
reduced the differences in deaths from CHD and all-cause mortality in the
trials (see Table 1).
|
THE PROBLEM OF ENDPOINTS
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A sign of a mature scientific strategy is consistency in the
criteria that
are used to measure its success. But one of the
most inconsistent aspects of
the statin trials is the choice
and variety of endpoints. Some
single-criterion items are found
in some of the trials but not in others, and
there is an evergrowing
list of items that are placed in varying combination
with each
other. All-cause mortality, the only measure not prone to diagnostic
variance,
is not popular. It is not even reported in a sub-study of the
Heart
Protection Study
(HPS)
13 and has to
be searched for in
several of the other trials.
Combination endpoints are often used—such as death, myocardial
infarction (MI), and stroke—and only the first event is counted. Most of
these combination endpoints are conceptually inconsistent. Some of the studies
add in a treatment, usually a form of revascularization. Treatments are
arbitrary physician-chosen entities, not instances of morbidity. Why this huge
palette of combination events? Could it be that the study designers are
searching for the combination that is most apt to yield a positive
result and avoid those that probably will not? This would not be the
scientific approach but would make sense if the aim was to make the study
appear highly successful. A recent review of 167 trials suggests just such a
possibility.14 It
found that ‘the inclusion of a clinician-driven outcome was predictive
of a statistically significant result for the primary composite
outcome.’ In other words, the studies would not have yielded positive
results if they had stuck to morbidity measures.
With respect to data on deaths the most important endpoint is all-cause
mortality. This can be manipulated only by fraud and is the one of primary
concern to the recipients of the treatment—are they less likely to die
soon, whatever the reason, if they take this drug? Of course, a detailed
breakdown of causes of death must also be included. For morbidity items, we
need to have clear information on the patient’s quality of life. If a
drug or other intervention neither extends life nor improves its overall
quality, then it is of no value. We need to focus on these two endpoints and
they should be kept separate, not put together in piecemeal fashion.
Regrettably, there is no rigorous reporting of all-cause morbidity, nor of
measurement of changes in overall quality of life, in any of the studies.
Rather, it is assumed that less CHD-related morbidity leads to less morbidity
overall.
Unfortunately, designating all-cause mortality and overall quality of life
as the primary endpoints is not ‘usual practice’ in the medical
research world. Such a shift from a medical industry perspective to a public
benefit perspective is long
overdue.15,16
|
PRESENTATION OF TRIAL DATA
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The statin trials found absolute differences of less than 1%
to a maximum
of 3.3% in all-cause mortality between the control
and treatment groups, and
from 1.1% to 4.7% in the most standard
combined event, fatal and nonfatal MI.
These are not impressive
results. But there is a way of making them look
impressive—namely,
by expressing the results as relative difference
rather than
as absolute difference. Take, for example, the LIPID
trial.
6 It involved
only patients with CHD (i.e. it was a secondary
prevention trial). The
difference in deaths between the statin
group and the placebo group was 3.1%
(14.1% of the placebo group
died and 11% of the statin group). But the impact
of these results
can be much magnified by expressing them as relative
differences:
‘The statin drug lowered the risk of death by 22%’
(11
is 22% lower than 14.1).
Another serious problem with the way the results are presented is that the
reader is often not told the number needed to treat (NNT) for one patient to
benefit. The NNTs range from around 30 in the 4S and LIPID trials to over 100
in the primary prevention trials. But this is not the information that
patients are likely to be given; instead, they will be told that they will
reduce their risk of death by about 30%. Presenting information to patients in
the form of relative risk will much increase their receptiveness to taking the
drug.
4S and LIPID were secondary prevention trials in patients with CHD and high
cholesterol. Because the participants were at high risk of death from CHD, the
NNTs are modest. Many such patients, perhaps a majority, may therefore agree
to take statins, even when given an unbiased version of the efficacy of the
drug. But the situation is altogether different when we turn our attention to
primary trials. Here, the participants have one or more risk factors for CHD
and are therefore at increased risk for the disease. However, their risk of
death from CHD is still much lower than that of participants in secondary
trials. As indicated in the Table, the NNT for such patients is much higher,
often well over 100. In these circumstances the way the ‘facts’
are presented is likely to have an enormous impact on whether the patient
agrees to take statins. Does the doctor say: ‘Mr Smith, if you take
statins this will reduce your risk of dying from heart disease by 30%’?
Or does she say: ‘Mr Smith, if you take statins, then in seven
years’ time there is a one chance in about 120 that your death will have
been prevented’? We argue that the latter is a much more honest version
of the clinical reality.
|
COST-EFFECTIVENESS OF STATINS
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Now let us look at the cost of preventing CHD by using statins.
The
simplest, minimum-assumption, calculation is based on three
factors—the
cost of the drug per year, the NNT, and the
length of the trials. The two
secondary prevention trials indicate
an NNT of about 30 to postpone one
death.
5,6
Using this figure
and a conservative estimate of the cost of the statin drugs
per
year of $500, we arrive at the cost of postponing one death
of $85 500
(500
x30
x5.7).
But that figure becomes much higher when we use data from the primary
prevention trials, as the NNTs are much higher. This has become especially
relevant because the latest NCEP III guidelines have considerably lowered the
eligibility requirements for using statin
drugs.17 This was
done by lowering the LDL-C threshold from 
4.1 mmol/L to 3.3 mmol/L in
conjunction with various risk factors, some of which were also modified to be
more inclusive. According to a detailed analysis it was estimated that the new
guidelines have the effect of expanding the number of people in the USA who
are now eligible for lipid lowering by drug therapy, which in most cases means
statins, from 15 million to 36 million, a jump of 140% at a
stroke.18 It is
noteworthy that the chair of the committee that wrote these guidelines as well
as five of the 13 members of the committee have received drug company funding.
The European recommendations are very similar, with targets of 5 mmol/L for
total cholesterol and 3 mmol/L for LDL.
The effect of widening the net for use of statins means that millions of
people at only modest risk of CHD will be eligible. For such people the cost
will be exceedingly high for the benefit achieved. We can illustrate this by
looking at a recent estimate. Using data from the HPS trials,
Marshall19 compared
the relative cost-effectiveness of aspirin, hypertension treatment, and a
statin. His calculations were based on costs in the UK and focused on patients
at a 10% risk of experiencing a major coronary event in the next five years.
He estimated that aspirin could prevent one CHD event (CHD death, angina, MI)
for £3500, compared with £61 400 for statins. Another important
point made by Marshall was that, if patients at high risk of CHD are given
aspirin, then the cost of preventing a coronary event by also giving statins
becomes much higher than the above figure. This is because, since the risk of
CHD has now been reduced by aspirin, the NNT for statins has increased, and
the cost of preventing a CHD event with a statin has therefore also much
increased. It is arguable that statins are cost-effective for the small
minority of people at especially high risk of CHD. However, the case for
statins becomes particularly dubious when we consider the impact of throwing
the net wider to include, for example, people in their fifties whose only risk
factor is a high cholesterol. In North America, the drug companies are
advertising directly to that section of the population, urging them to ask
their doctor for a prescription for statins. For people at that risk level,
the cost of statins translates to more than $300 000 to prevent a major CHD
event. In the UK National Health Service, statins are at present available
only to people whose global risk is greater than 3% per year—a figure
much influenced by the cost of the drugs and other pressures on the exchequer.
In other European countries, clinicians have more latitude. This year the UK
Government has tacitly acknowledged a wider demand by making one of the
statins, simvastatin, available without prescription. Presumably the British
public will in due course be exposed to a direct marketing campaign on North
American lines. The diversion of incomes, whether personal or national, to
such high-cost low-efficacy interventions is always something to be resisted.
What is the opportunity cost of such expenditure? In national terms the NNT
required to lift a young person out of poverty, thus resulting in better
health and more productivity, is probably much superior.
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CONCLUSIONS
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The design of the trials has not involved the testing of the
value of
statin drugs relative to that of guideline-recommended
promotion of lifestyle
changes. The small differences favouring
the drug have been magnified by the
manner of presentation of
results, most notably by the use of relative
differences between
statins and placebo groups rather than absolute
differences.
A broad societal perspective is lacking with regard to acceptable
costs
of these and other medical interventions. Lowering the threshold
to make
much larger numbers of people eligible for drug therapy
has the effect of
making statins an extremely expensive means
of preventing heart disease. The
case for statin drugs, especially
for primary prevention, has not been
made.
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REFERENCES
|
|---|
- http://nf4.newsfutures.com/bk/market/grpIndex.html?_gid=14.
Accessed 2 May, 2004
- Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B.
Placebo-controlled trials and the Declaration of Helsinki.
Lancet2002; 359:1337
–40[Medline]
- European Atherosclerosis Society. Strategies for the prevention of
coronary heart disease: a policy statement. Eur Heart
J 1987;8:77
–88[Abstract/Free Full Text]
- The Expert Panel. Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Arch Intern Med1988; 148:36
–69[Abstract]
- Scandinavian Simvastatin Survival Study Group. Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet1994; 344:1383
–9[Medline]
- The Long-Term Intervention with Pravastatin in Ischemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. N Engl J Med1998; 339:1349
–57[Abstract/Free Full Text]
- Sacks FM, Pfeffer MA, Moye LA. The effect of pravastatin on
coronary events after myocardial infarction in patients with average
cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
N Engl J Med1996; 335:1001
–9[Abstract/Free Full Text]
- Lewis SJ, Moye LA, Sacks FM, et al. Effect of pravastatin
on cardiovascular events in older patients with myocardial infarction and
cholesterol levels in the average range. Results of the Cholesterol and
Recurrent Events (CARE) trial. Ann Intern Med1998; 129:681
–9[Abstract/Free Full Text]
- Shepherd J, Gobbe SM, Ford I, et al. Prevention of
coronary heart disease with pravastatin in men with hypercholesterolemia. West
of Scotland Coronary Prevention Study Group. N Engl J
Med 1995;333:1301
–7[Abstract/Free Full Text]
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial. Major outcomes in moderately hypercholesterolemic,
hypertensive patients randomized in pravastatin vs usual care: The
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT-LLT). JAMA2002; 288:2998
–3007[Abstract/Free Full Text]
- Downs JR, Clearfield M, Weis S, et al. Primary prevention
of acute coronary events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary
Atherosclerosis Prevention Study. JAMA1998; 279:1615
–22[Abstract/Free Full Text]
- Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk
individuals: a randomised placebo-controlled trial.
Lancet2002; 360:7
–22[Medline]
- Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection
Study Collaborative Group. MRC/BHF Heart Protection Study of
cholesterol-lowering with simvastatin in 5963 people with diabetes: a
randomised placebo-controlled trial. Lancet2003; 361:2005
–16[Medline]
- Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite
outcomes in randomized trials: greater precision but with greater uncertainty?
JAMA2003; 289:2554
–9[Abstract/Free Full Text]
- Thompson A, Temple N. Ethics, Medical Research, and
Medicine. Dordrecht: Kluwer Academic Press,2001
- Thompson A, Temple N, eds. Ethics, Medical Research, and
Medicine: Commercialism Versus Environmentalism and Social
Justice. London: Kluwer Academic, 2001
- National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). Third Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Circulation 2002;
106:3143
–421[Free Full Text]
- Fedder DO, Koro CE, L’Italien GJ. New National Cholesterol
Education Program III guidelines for primary prevention lipid-lowering drug
therapy: projected impact on the size, sex, and age distribution of the
treatment-eligible population. Circulation2002; 105:152
–6[Abstract/Free Full Text]
- Marshall T. Coronary heart disease prevention: insights from
modelling incremental cost effectiveness. BMJ2003; 327:1264
–7[Abstract/Free Full Text]
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INTRODUCTION
THE COMPARISON GROUP: BEST...
