Absolute risk and non-lipid effects



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.
 
B

Bob

Guest
Zee wrote:

> 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 =96 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 =96
> perhaps most importantly =96 used the same drug, at th=
e
> same dose, in all patients. So it actually means
> something.

Um, the J-LIT trial did show correlations. From the
abstract:

"The aim of the study was to determine the relationship
between the=20 occurrence of CHD and the serum lipid
concentrations during low-dose=20 simvastatin treatment.
Simvastatin reduced serum concentrations of=20 total
cholesterol (TC), low-density lipoprotein-cholesterol (LDL-
C)=20 and triglyceride (TG), by 18.4%, 26.8% and 16.1% on
average,=20 respectively, during the treatment period. The
risk of coronary events=20 was higher when the average TC
concentration was >=3D240mg/dl and the=20 average LDL-C
concentration was >=3D160mg/dl. The incidence of coronary=20
events increased in the patients with TG concentration
>=3D300mg/dl=20 compared with patients with TG concentration
<150 mg/dl. The=20 high-density lipoprotein cholesterol (HDL-
C) inversely correlated with=20 the risk of coronary events.
The J-curve association was observed=20 between average TC
or LDL-C concentrations and total mortality."

In the Discussion part of the paper, the authors wrote:

"The present study demonstrates a relationship between serum
lipid=20 concentrations and the incidence of coronary events
in Japanese=20 patients with hypercholesterolemia under low-
dose simvastatin=20 treatment. A reasonable strategy to
prevent coronary events in=20 Japanese hypercholesterolemic
patients without prior CHD under=20 low-dose statin
treatment might be to regulate the serum lipid=20
concentrations to at least <240 mg/dl for TC, <160 mg/dl for
LDL-C and=20 <300mg/dl for TG and >40 mg/dl for HDL-C."

> 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.

Can't imagine how you came to this conclusion.

Bob

Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT Study
Group.=20 Japan Lipid Intervention Trial. Large scale cohort
study of the=20 relationship between serum cholesterol
concentration and coronary=20 events with low-dose
simvastatin therapy in Japanese patients with=20
hypercholesterolemia. Circ J 2002;66(12):1087-95.
 
B

Bob

Guest
Zee wrote:

> 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 =96 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 =96
> perhaps most importantly =96 used the same drug, at th=
e
> same dose, in all patients. So it actually means
> something.

Um, the J-LIT trial did show correlations. From the
abstract:

"The aim of the study was to determine the relationship
between the=20 occurrence of CHD and the serum lipid
concentrations during low-dose=20 simvastatin treatment.
Simvastatin reduced serum concentrations of=20 total
cholesterol (TC), low-density lipoprotein-cholesterol (LDL-
C)=20 and triglyceride (TG), by 18.4%, 26.8% and 16.1% on
average,=20 respectively, during the treatment period. The
risk of coronary events=20 was higher when the average TC
concentration was >=3D240mg/dl and the=20 average LDL-C
concentration was >=3D160mg/dl. The incidence of coronary=20
events increased in the patients with TG concentration
>=3D300mg/dl=20 compared with patients with TG concentration
<150 mg/dl. The=20 high-density lipoprotein cholesterol (HDL-
C) inversely correlated with=20 the risk of coronary events.
The J-curve association was observed=20 between average TC
or LDL-C concentrations and total mortality."

In the Discussion part of the paper, the authors wrote:

"The present study demonstrates a relationship between serum
lipid=20 concentrations and the incidence of coronary events
in Japanese=20 patients with hypercholesterolemia under low-
dose simvastatin=20 treatment. A reasonable strategy to
prevent coronary events in=20 Japanese hypercholesterolemic
patients without prior CHD under=20 low-dose statin
treatment might be to regulate the serum lipid=20
concentrations to at least <240 mg/dl for TC, <160 mg/dl for
LDL-C and=20 <300mg/dl for TG and >40 mg/dl for HDL-C."

> 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.

Can't imagine how you came to this conclusion.

Bob

Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT Study
Group.=20 Japan Lipid Intervention Trial. Large scale cohort
study of the=20 relationship between serum cholesterol
concentration and coronary=20 events with low-dose
simvastatin therapy in Japanese patients with=20
hypercholesterolemia. Circ J 2002;66(12):1087-95.
 
L

listener

Guest
On 11 Mar 2004 05:14:35 -0800, [email protected] (Zee) wrote:

>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?
>
>
>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.

About J-LIT:

"The study involved ...a total of 47,294 men (32%) and
menopausal women (68%) *aged = 70 yrs* with total
cholesterol (TC) level = 220
mg/dl. All subjects had no prior coronary artery disease
(CAD) and had not been treated with any cholesterol-
lowering therapy."

The study did show the importance of cholesterol-lowering
therapy for preventing *MI*. (Even with a already low
incidence of MI the Japanese hypercholesterolemia
population.)

Kendrick is hung up on *mortality* and while the study did
not see a lowering-LDL-drop in mortality correlation he's
seems to not be able to see the forest for the trees. He's
quite a skeptic, from what I've read. (Perhaps bordering a
bit on the "kooky" side)

By the way, over the course of the 6-year study ONE death
and 9 cases of hospitalization occurred as serious adverse
reaction to the statin. That's (0.02%)...Oh my.

It's important to remember that statins have been shown to
prevent the activation of monocytes into macrophages,
inhibit the production of pro-inflammatory cytokines, C-
reactive protein, and cellular adhesion molecules, and
decrease the adhesion of monocyte to endothelial cells. The
benefit of statins may be their anti-inflammatory effect,
and the lowering of cholesterol may be an interesting side
effect. LDLs appear to be harmful when they are oxidized.
Without a pro-oxidant or pro-inflammatory environment
perhaps elevated lipids are significantly less of a threat,
and perhaps we should be emphasizing the type of plaque,
inflammatory milieu, and endothelial dysfunction rather than
circulating lipids per se.

n.
 
L

listener

Guest
On 11 Mar 2004 05:14:35 -0800, [email protected] (Zee) wrote:

>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?
>
>
>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.

About J-LIT:

"The study involved ...a total of 47,294 men (32%) and
menopausal women (68%) *aged = 70 yrs* with total
cholesterol (TC) level = 220
mg/dl. All subjects had no prior coronary artery disease
(CAD) and had not been treated with any cholesterol-
lowering therapy."

The study did show the importance of cholesterol-lowering
therapy for preventing *MI*. (Even with a already low
incidence of MI the Japanese hypercholesterolemia
population.)

Kendrick is hung up on *mortality* and while the study did
not see a lowering-LDL-drop in mortality correlation he's
seems to not be able to see the forest for the trees. He's
quite a skeptic, from what I've read. (Perhaps bordering a
bit on the "kooky" side)

By the way, over the course of the 6-year study ONE death
and 9 cases of hospitalization occurred as serious adverse
reaction to the statin. That's (0.02%)...Oh my.

It's important to remember that statins have been shown to
prevent the activation of monocytes into macrophages,
inhibit the production of pro-inflammatory cytokines, C-
reactive protein, and cellular adhesion molecules, and
decrease the adhesion of monocyte to endothelial cells. The
benefit of statins may be their anti-inflammatory effect,
and the lowering of cholesterol may be an interesting side
effect. LDLs appear to be harmful when they are oxidized.
Without a pro-oxidant or pro-inflammatory environment
perhaps elevated lipids are significantly less of a threat,
and perhaps we should be emphasizing the type of plaque,
inflammatory milieu, and endothelial dysfunction rather than
circulating lipids per se.

n.
 
A

Al. Lohse

Guest
This is great. Perhaps the first time in cholesterol science
history in which a contradiction exists that favours statin
drug treatment and cholesterol reduction. Certainly,
resolving this contradiction will make the science stronger.

Contradictions which counter drug use and cholesterol
reduction are routinely ignored with ample disregard to the
impartiality of the researchers who make those discoveries.
Let us not ignore this one. It may help to resolve the
cholesterol dichotomy.

The Japanese study appears, as well, to have been
Publicly Funded!

A.L.

"Bob (this one)" wrote:
> =

> Zee wrote:
> =

> > 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 =96 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 =96 perhaps most importantly =96 used the
> > same drug, at =
the
> > same dose, in all patients. So it actually means
> > something.
> =

> Um, the J-LIT trial did show correlations. From the
> abstract:
> =

> "The aim of the study was to determine the relationship
> between the occurrence of CHD and the serum lipid
> concentrations during low-dose simvastatin treatment.
> Simvastatin reduced serum concentrations of total
> cholesterol (TC), low-density lipoprotein-cholesterol (LDL-
> C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on
> average, respectively, during the treatment period. The
> risk of coronary events was higher when the average TC
> concentration was >=3D240mg/dl and the average LDL-C
> concentration was >=3D160mg/dl. The incidence of coronary=

> events increased in the patients with TG concentration
> >=3D300mg/dl compared with patients with TG concentration
> <150 mg/dl. The high-density lipoprotein cholesterol (HDL-
> C) inversely correlated with the risk of coronary events.
> The J-curve association was observed between average TC or
> LDL-C concentrations and total mortality."
> =

> In the Discussion part of the paper, the authors wrote:
> =

> "The present study demonstrates a relationship between
> serum lipid concentrations and the incidence of coronary
> events in Japanese patients with hypercholesterolemia
> under low-dose simvastatin treatment. A reasonable
> strategy to prevent coronary events in Japanese
> hypercholesterolemic patients without prior CHD under low-
> dose statin treatment might be to regulate the serum lipid
> concentrations to at least <240 mg/dl for TC, <160 mg/dl
> for LDL-C and <300mg/dl for TG and >40 mg/dl for HDL-C."
> =

> > 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.
> =

> Can't imagine how you came to this conclusion.
> =

> Bob
> =

> Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT Study
> Group. Japan Lipid Intervention Trial. Large scale cohort
> study of the relationship between serum cholesterol
> concentration and coronary events with low-dose
> simvastatin therapy in Japanese patients with
> hypercholesterolemia. Circ J 2002;66(12):1087-95.
 
A

Al. Lohse

Guest
This is great. Perhaps the first time in cholesterol science
history in which a contradiction exists that favours statin
drug treatment and cholesterol reduction. Certainly,
resolving this contradiction will make the science stronger.

Contradictions which counter drug use and cholesterol
reduction are routinely ignored with ample disregard to the
impartiality of the researchers who make those discoveries.
Let us not ignore this one. It may help to resolve the
cholesterol dichotomy.

The Japanese study appears, as well, to have been
Publicly Funded!

A.L.

"Bob (this one)" wrote:
> =

> Zee wrote:
> =

> > 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 =96 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 =96 perhaps most importantly =96 used the
> > same drug, at =
the
> > same dose, in all patients. So it actually means
> > something.
> =

> Um, the J-LIT trial did show correlations. From the
> abstract:
> =

> "The aim of the study was to determine the relationship
> between the occurrence of CHD and the serum lipid
> concentrations during low-dose simvastatin treatment.
> Simvastatin reduced serum concentrations of total
> cholesterol (TC), low-density lipoprotein-cholesterol (LDL-
> C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on
> average, respectively, during the treatment period. The
> risk of coronary events was higher when the average TC
> concentration was >=3D240mg/dl and the average LDL-C
> concentration was >=3D160mg/dl. The incidence of coronary=

> events increased in the patients with TG concentration
> >=3D300mg/dl compared with patients with TG concentration
> <150 mg/dl. The high-density lipoprotein cholesterol (HDL-
> C) inversely correlated with the risk of coronary events.
> The J-curve association was observed between average TC or
> LDL-C concentrations and total mortality."
> =

> In the Discussion part of the paper, the authors wrote:
> =

> "The present study demonstrates a relationship between
> serum lipid concentrations and the incidence of coronary
> events in Japanese patients with hypercholesterolemia
> under low-dose simvastatin treatment. A reasonable
> strategy to prevent coronary events in Japanese
> hypercholesterolemic patients without prior CHD under low-
> dose statin treatment might be to regulate the serum lipid
> concentrations to at least <240 mg/dl for TC, <160 mg/dl
> for LDL-C and <300mg/dl for TG and >40 mg/dl for HDL-C."
> =

> > 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.
> =

> Can't imagine how you came to this conclusion.
> =

> Bob
> =

> Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT Study
> Group. Japan Lipid Intervention Trial. Large scale cohort
> study of the relationship between serum cholesterol
> concentration and coronary events with low-dose
> simvastatin therapy in Japanese patients with
> hypercholesterolemia. Circ J 2002;66(12):1087-95.
 
Z

Zee

Guest
"Bob (this one)" <[email protected]> wrote in message news:<[email protected]>...
> Zee wrote:
>
> Um, the J-LIT trial did show correlations. From the
> abstract:
>
> "The aim of the study was to determine the relationship
> between the occurrence of CHD and the serum lipid
> concentrations during low-dose simvastatin treatment.
> Simvastatin reduced serum concentrations of total
> cholesterol (TC), low-density lipoprotein-cholesterol (LDL-
> C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on
> average, respectively, during the treatment period. The
> risk of coronary events was higher when the average TC
> concentration was >=240mg/dl and the average LDL-C
> concentration was >=160mg/dl. The incidence of coronary
> events increased in the patients with TG concentration
> >=300mg/dl compared with patients with TG concentration
> <150 mg/dl. The high-density lipoprotein cholesterol (HDL-
> C) inversely correlated with the risk of coronary events.
> The J-curve association was observed between average TC or
> LDL-C concentrations and total mortality."
>
> In the Discussion part of the paper, the authors wrote:
>
> "The present study demonstrates a relationship between
> serum lipid concentrations and the incidence of coronary
> events in Japanese patients with hypercholesterolemia
> under low-dose simvastatin treatment. A reasonable
> strategy to prevent coronary events in Japanese
> hypercholesterolemic patients without prior CHD under low-
> dose statin treatment might be to regulate the serum lipid
> concentrations to at least <240 mg/dl for TC, <160 mg/dl
> for LDL-C and <300mg/dl for TG and >40 mg/dl for HDL-C."
>
> > 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.
>
> Can't imagine how you came to this conclusion.

Bob

Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT
Study Group.
> Japan Lipid Intervention Trial. Large scale cohort study
> of the relationship between serum cholesterol
> concentration and coronary events with low-dose
> simvastatin therapy in Japanese patients with
> hypercholesterolemia. Circ J 2002;66(12):1087-95.

$$$$$$$$$$$$$$$$$tatin$$$$$$$$$$$4

I didn't. This is Kendrick's work and appropos the newsgroup
topic, no? Why don't you e-mail Kendrick with your differing
views, and tell us what he says. He's approachable. Would be
of great interest to us all. [email protected]

This article appeared today, following the one above.

PROVE-IT AND BEYOND

A Massive Nail In The Coffin Of The Cholesterol, Or LDL,
Hypothesis?

By RFD Columnist Dr. Malcolm Kendrick

(email - [email protected] )

See Also: 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.

For those 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.

A very 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.

In this 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.

This, again, 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' analysis.

One of the things they looked at was the progression of
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.

Dr Steve Nissen, lead investigator from the Cleveland
Clinic noted:

‘Surprisingly, 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.'

What does 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.

Which is, 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 follows:

Statins reduce the risk of heart disease 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.
 
Z

Zee

Guest
"Al. Lohse" <[email protected]> wrote in message news:<[email protected]>...
> This is great. Perhaps the first time in cholesterol
> science history in which a contradiction exists that
> favours statin drug treatment and cholesterol reduction.
> Certainly, resolving this contradiction will make the
> science stronger.
>
> Contradictions which counter drug use and cholesterol
> reduction are routinely ignored with ample disregard to
> the impartiality of the researchers who make those
> discoveries. Let us not ignore this one. It may help to
> resolve the cholesterol dichotomy.
>
> The Japanese study appears, as well, to have been
> Publicly Funded!
>
> A.L.

I wish those who share your ability for intelligent
questing discussion on this would engage you Al. I cannot,
as I have pointed out to my considerable humiliation,
remember what it is I am trying to figure out long enough
to figure it out. But if Bob Pastorio can, why does he not
answer you. Where is Jim Chinnis on this? What does Patick
Blanchard have to say. I would like to benefit from what
these fine minds have to say.

I'm trying to rehab cognitively. Let me benefit vicariously
from your discussion.

B'adant

>
> "Bob (this one)" wrote:
> >
>
> > Zee wrote:
> >
>
> > > 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.
> >
>
> > Um, the J-LIT trial did show correlations. From the
> > abstract:
> >
>
> > "The aim of the study was to determine the relationship
> > between the occurrence of CHD and the serum lipid
> > concentrations during low-dose simvastatin treatment.
> > Simvastatin reduced serum concentrations of total
> > cholesterol (TC), low-density lipoprotein-cholesterol
> > (LDL-C) and triglyceride (TG), by 18.4%, 26.8% and 16.1%
> > on average, respectively, during the treatment period.
> > The risk of coronary events was higher when the average
> > TC concentration was >=240mg/dl and the average LDL-C
> > concentration was >=160mg/dl. The incidence of coronary
>
> > events increased in the patients with TG concentration
> > >=300mg/dl compared with patients with TG concentration
> > <150 mg/dl. The high-density lipoprotein cholesterol (HDL-
> > C) inversely correlated with the risk of coronary
> > events. The J-curve association was observed between
> > average TC or LDL-C concentrations and total mortality."
> >
>
> > In the Discussion part of the paper, the authors wrote:
> >
>
> > "The present study demonstrates a relationship between
> > serum lipid concentrations and the incidence of coronary
> > events in Japanese patients with hypercholesterolemia
> > under low-dose simvastatin treatment. A reasonable
> > strategy to prevent coronary events in Japanese
> > hypercholesterolemic patients without prior CHD under
> > low-dose statin treatment might be to regulate the serum
> > lipid concentrations to at least <240 mg/dl for TC, <160
> > mg/dl for LDL-C and <300mg/dl for TG and >40 mg/dl for
> > HDL-C."
> >
>
> > > 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.
> >
>
> > Can't imagine how you came to this conclusion.
> >
>
> > Bob
> >
>
> > Source: Matsuzaki M, Kita T, Mabuchi H, et al; J-LIT
> > Study Group. Japan Lipid Intervention Trial. Large scale
> > cohort study of the relationship between serum
> > cholesterol concentration and coronary events with low-
> > dose simvastatin therapy in Japanese patients with
> > hypercholesterolemia. Circ J 2002;66(12):1087-95.
 
L

listener

Guest
On 12 Mar 2004 11:14:15 -0800, [email protected] (Zee) wrote:

>"Al. Lohse" <[email protected]> wrote in message
>news:<[email protected]>...
>> This is great. Perhaps the first time in cholesterol
>> science history in which a contradiction exists that
>> favours statin drug treatment and cholesterol reduction.
>> Certainly, resolving this contradiction will make the
>> science stronger.
>>
>> Contradictions which counter drug use and cholesterol
>> reduction are routinely ignored with ample disregard to
>> the impartiality of the researchers who make those
>> discoveries. Let us not ignore this one. It may help to
>> resolve the cholesterol dichotomy.
>>
>> The Japanese study appears, as well, to have been
>> Publicly Funded!
>>
>> A.L.
>
>
>I wish those who share your ability for intelligent
>questing discussion on this would engage you Al. I cannot,
>as I have pointed out to my considerable humiliation,
>remember what it is I am trying to figure out long enough
>to figure it out. But if Bob Pastorio can, why does he not
>answer you. Where is Jim Chinnis on this? What does Patick
>Blanchard have to say. I would like to benefit from what
>these fine minds have to say.
>
>I'm trying to rehab cognitively. Let me benefit vicariously
>from your discussion.
>
>
>B'adant

Engagement is futile. Your positions are all too clear and
as immovable as a mountain.

L.