published in RedFlagsDaily)
A Massive Nail In The Coffin Of The Cholesterol, Or LDL,
who follow my ramblings, I felt the need for a very rapid
follow-up to my column on the PROVE-IT study, which has been
hailed as proof that the more you lower LDL levels the greater
the protection against heart disease, and death.
similar study to PROVE–IT was done, looking at the effect of
pravastatin and atorvastatin on the growth of the
atherosclerotic plaque. This was the REVERSAL study,
published late last year, and a review of this trial was sent to
me today. So I thought I should share it with you.
study, as with the PROVE-IT study, atorvastatin reduced the LDL
to a greater degree than pravastatin – on average. And the
progression rate of atherosclerosis was reduced more by
atorvastatin than pravastatin.
would seem to prove that greater LDL lowering provides greater
protection against CHD, and death. However, the investigators
decided to look at the data in more detail in a ‘post-hoc'
One of the
things they looked at was the progres
atherosclerosis in those patients taking pravastatin who
achieved the greatest lowering of their LDL level. Down to
88mg/dl – similar to the level achieved on atorvastatin.
Nissen, lead investigator from the Cleveland Clinic noted:
despite attaining a low LDL level on pravastatin, these patients
showed highly significant progression for percent atheroma
volume and percent obstructive volume… At any LDL level,
progression was less on atorvastatin than on pravastatin. When I
started this study, I believed that any reduction in progression
would just be due to lower LDL levels, but now I'm not so sure.
This analysis suggests that it may be more than just LDL it
seems to be the drug as well…. Yes, this is a post-hoc
analysis and should be considered hypothesis generating,' but I
would say it is a robust finding.'
this mean? It means that atorvastatin protects against CHD more
effectively than pravastatin. It also means that the degree of
protection has absolutely nothing to do with the reduction in
LDL levels. The protection is provided by a direct drug effect.
or should be, a massive nail in the coffin of the cholesterol,
or LDL, hypothesis. Of course, it won't be.
If I were
to summarise all of the statin trials up till now it would be as
Statins reduce the risk of
They reduce the risk of heart
disease regardless of the starting level of LDL, and regardless
of how much they lower the LDL
Statins protect in conditions
where a raised LDL is not a risk factor e.g. stroke
Statins reduce the overall risk
of death in a small group of very high risk men e.g. those who
have already had an MI, or who have diabetes
Statins do no reduce the
overall risk of death in women – at all, regardless of their
level of risk.
Conclusion: Statins work through direct effects on
atherosclerotic plaque development. This effect has nothing to
do with lowering LDL levels.
PROVE IT – PROVED
published in RedFlagsDaily)
New Study Data Has
Researchers And “Rent-A-Quote” Doctors Pushing For More
Intensive Cholesterol-Lowering Treatment. This Is Massive Hype.
implications of this turning point – that is, of the new era
of intensive statin therapy – are profound. Even today, only a
fraction of the patients who should be treated with a statin are
actually receiving such therapy…. More than 200 million people
worldwide meet the criteria for treatment, but fewer than 25
million take statins.'
- Dr Eric
Topol Cleveland Clinic
At last, to
massive cheers from all Pfizer shareholders everywhere, it has
been proved that the more you lower the LDL level (bad
cholesterol) the greater the protection against heart disease,
and death, and world poverty and… sorry, got a little carried
away in the emotion of the moment.
it has been known that statins protect against heart disease,
and in a select groups of very high risk patients, it has been
confirmed that statins may even reduce the death rate. But
no-one has ever managed to demonstrate that the protection was
related to the degree of LDL lowering. A fact that may surprise
you, but it's true.
however, in the ever so aptly named PR avastatin
O r Ator V astatin E valuation
and I nfection s T udy PROVE-IT
, (talk about a tortuous anagram) all remaining doubts
have been swept away in an avalanche of data. Results have been
produced that will, according to Dr Eric ‘rent-a-quote' Topol,
‘Herald a shake-up in the field of cardiovascular prevention.'
Hmmm. I beg to differ.
by looking a little more closely at the PROVE-IT study. What it
was and what it showed.
the investigators took 4,162 patients who had been in hospital
following an MI, or unstable angina (almost, but not quite an
MI). They then split the group in half and gave one half
pravastatin (made by BMS), and the other half atorvastatin (made
by Pfizer). As expected LDL level, or ‘bad cholesterol' level,
was reduced to a greater extent in the atorvastatin group.
LDL in the
treated pravastatin group: average 95 mg/dl
(range 79 – 113)
LDL in the
treated atorvastatin group: average 62 mg/dl
(range 50 – 79)
in the atorvastatin group there was a thirty two percent greater
reduction in LDL levels, and there was also a sixteen percent
greater reduction in – well – almost everything you can
think of: all cause mortality, MI, unstable angina, hospital
readmission, interventional procedures. You name it, it was all
when they say a sixteen percent reduction, they actually mean a
sixteen percent reduction in relative risk. Which, as you will
hopefully all know by now, may mean something – or nothing?
shall be fair. Just focusing on all-cause mortality which, I
think, is the most important figure to choose. The absolute
reduction in the rate of death from taking atorvastatin, rather
than pravastatin, was one percent, a decrease from 3.2% to 2.2%,
over twenty four months. Or, to put it another way, a 0.5%
absolute risk reduction per year.
as mind-boggling as you would hope, but in line with previous
studies of this type. So what are the problems with this study?
Apart from massive over-hype.
the most basic problem with the study is the old ‘two
variables' conundrum. It is true that those with the greatest
LDL lowering were protected against death.
you may have noticed, those who were protected not only had a
greater degree of LDL lowering, THEY WERE ALSO ON A DIFFERENT
DRUG! which is rather important, yet seems to have been swept
aside on a wave of hype.
if you really want to prove that the more you lower the LDL
level, the greater the protection, then you must use
the same drug. This achieves an absolutely critical requirement
of any scientific experiment, which is to remove all possible
an experiment of this type, you should not only use the same
drug, you should also use the same dose of the drug; then group
patients by how much the LDL was lowered, then see if the
protection against death is related to the degree of LDL
lowering. This would remove the possibility that a higher dose
of the same drug protects against CHD through other non-lipid
effects. Which is kind of important as, over the last few years,
it has been found that statins do a great deal more than lower
addition to their lipid-modulating properties, statins have a
large number of beneficial cardiovascular effects that have
emerged over time and that were not anticipated during drug
development…. By acting on the vessel wall, statins may
prevent lesion initiation and repair injuries, enhance
myocardial perfusion, slow lesion progression, and prevent
coronary occlusion. They may also directly reduce myocardial
damage, favor myocardial repair, and protect against immune
injury.' Davignon J. Curr Atheroscler Rep. 2004 Jan
for the PROVE-IT study to mean anything, requires that
atorvastatin and pravastatin are identical in all actions, only
differing in the amount that they lower LDL. If they do have
other direct, and drug specific effects, which could explain the
difference in protection from heart disease, then all the
PROVE-IT proved was that atorvastatin provides more protection
from heart disease than pravastatin – and this may have
nothing to do with the impact on LDL.
Earth didn't the investigators choose to use different doses of
atorvastatin to lower the LDL by different amounts? Or, even
better, use the same dose of atorvastatin then group patients by
the degree of LDL lowering achieved? What stopped them from
doing either of these things?
There is no
practical reason why this couldn't have been done, and from a
scientific perspective it would have been infinitely preferable.
In fact, it would have prevented the study from being a
completely meaningless load of rubbish.
study presently stands, because they used different drugs,
anyone can make the case that the benefits seen in the patients
on atorvastatin had nothing to do with greater LDL lowering;
they were purely due to direct drug effects of atorvastatin. And
it is impossible for the authors to argue that this is not the
addition, there is some very powerful evidence out there that
directly contradicts the hypothesis that the degree of LDL
lowering, and the protection against death are connected. This
evidence comes from across the ocean, and is provided by another
study which – perhaps to no-one's great surprise, attracted
very little attention at all.
A couple of
years ago a much larger study than PROVE-IT finished in Japan.
The Japan Lipid Intervention Trial (J-LIT) Matsuzaki M et al
Circ J 2002;66: 1087 - 1095 . In this trial
over thirty thousand patients with raised LDL levels were put on
simvastatin at the single dose of 5mg daily, and then patients
were grouped by the degree of LDL lowering achieved – the
ideal study if you want to remove all variables.
would expect, although everyone took the same dose of the drug,
not everyone's LDL level responded the same way. Some patients
had no reduction in LDL levels (I would suggest that these were
the patients who didn't bother taking the drug). Some had a
moderate fall in LDL, and some had very large LDL reductions.
for a nice, simple, single variable analysis to be done. The
drug was the same in all patients, the drug dose was the same in
all patients, and the patients were all chosen to provide a
homogeneous sample with a similar starting level of LDL. The
only thing that was different was the amount by which the LDL
fell. Nice and simple. And what, gentle readers, do you think it
that there is no correlation whatsoever between the amount of
LDL lowering, and death rate. None. This, please remember, in a
study that had ten times as many patients, lasted almost three
times as long and – perhaps most importantly – used the same
drug, at the same dose, in all patients. So it actually means
what did PROVE-IT really prove? It proved that atorvastatin
protects against heart disease and death better than pravastatin.
What it most certainly did not prove is that the more you lower
the LDL level the greater the protection.
J-LIT is the only study done so
far that has looked scientifically, rather than marketingly, at
the correlation between LDL lowering and protection against
death, and it PROVED-THAT there is no connection at all.
More essays by Malcolm Kendrick