Absolute risk and non-lipid effects

Discussion in 'Health and medical' started by Zee, Mar 11, 2004.

  1. Zee

    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.
     
    Tags:


  2. Bob

    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.
     
  3. Bob

    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.
     
  4. listener

    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.
     
  5. listener

    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.
     
  6. Al. Lohse

    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.
     
  7. Al. Lohse

    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.
     
  8. Zee

    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.
     
  9. Zee

    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.
     
  10. listener

    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.
     
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