Z
Zee
Guest
Kendrick asks the big one and comes up with 0.5 per cent
absolute risk reduction. Oh my.
http://www.redflagsweekly.com/kendrick/2004_mar10.html
PROVE IT – PROVED WHAT?
New Study Data Has Researchers And "Rent-A-Quote" Doctors
Pushing For More Intensive Cholesterol-Lowering Treatment.
This Is Massive Hype.
By RFD Columnist Dr. Malcolm Kendrick
(email - [email protected] )
‘The 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.
For years 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.
Now, 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.
Let's start by looking a little more closely at the PROVE-IT
study. What it was and what it showed.
In PROVE-IT 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 short, 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 quite wonderful.
Of course 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?
However, I 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.
Maybe not 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.
I suppose 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. However,
as 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.
In reality, 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 uncontrolled variables.
Ideally, in 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 LDL.
‘In 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
Presently, 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.
Why on 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.
As this 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 case.
In 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.
As you 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.
This allowed 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 showed.
It showed 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 something.
In contrast 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.
absolute risk reduction. Oh my.
http://www.redflagsweekly.com/kendrick/2004_mar10.html
PROVE IT – PROVED WHAT?
New Study Data Has Researchers And "Rent-A-Quote" Doctors
Pushing For More Intensive Cholesterol-Lowering Treatment.
This Is Massive Hype.
By RFD Columnist Dr. Malcolm Kendrick
(email - [email protected] )
‘The 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.
For years 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.
Now, 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.
Let's start by looking a little more closely at the PROVE-IT
study. What it was and what it showed.
In PROVE-IT 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 short, 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 quite wonderful.
Of course 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?
However, I 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.
Maybe not 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.
I suppose 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. However,
as 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.
In reality, 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 uncontrolled variables.
Ideally, in 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 LDL.
‘In 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
Presently, 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.
Why on 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.
As this 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 case.
In 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.
As you 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.
This allowed 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 showed.
It showed 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 something.
In contrast 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.