Re: Statins again.
- From: berniebagelbear@xxxxxxxxx
- Date: 20 May 2007 19:46:36 -0700
On May 6, 1:22 pm, David Rind <d...@xxxxxxxxxxxxxxxxxxxxx> wrote:
Jason wrote:
In article <f1l79j$dq...@xxxxxxxxxxxxxxxxx>, David Rind
<d...@xxxxxxxxxxxxxxxxxxxxx> wrote:
tonyzs...@xxxxxxxxx wrote:
Thank you David for taking the trouble to post details of this meta
analysis. I am sorry not to have acknowldeged this sooner.
One slight difficulty: I have tried to unerth the actual number of
deaths and cardiac events, so that a comparison can be made with
relative reductions and absolute ones. As I cannot gain access to
these data on the internet is it possible for you to provide me with
this information?
You generally can't look at absolute rates in a meta-analysis, because
the baseline rates vary so much across different populations. Typically
a meta-analysis tests for, and then assumes, that the relative
reductions are stable across the different studies but that the absolute
rates differ.
If you are trying to figure out how much benefit a statin might have in
a given individual, calculate the 10-year-risk of an event (cardiac
event or death) using a risk score such as the Framingham score, and
then use the relative risk reductions posted earlier to calculate an
absolute risk reduction. The absolute reductions even in secondary
prevention are typically small (5 to 10 percent) but in a range that
most people would find clinically important if it were them.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
David,
One of the problems is that many doctors do not seem to realize that high
dose statins (eg 80 mg Lipitor) are more likely to cause serious side
effects (eg major muscle pain, memory problems) than low dose statins (eg
5 mg Lipitor). It may take longer for a patient's chol. levels to come
down to normal but in the long run--it would be much less likely that
patients would develop serious side effects. I was shocked when one of my
neighbors was started off on a 80 mg dose of Lipitor. His chol. levels
were only slighly above the reference range. I doubt that his doctor
realized that he could have caused my neighbor to develop serious side
effects. Do you agree or disagree?
jason
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I don't know what your neighbor was being treated for, so it's hard to
have a firm opinion.
If we're talking about someone with known stable CHD, the TNT and IDEAL
trials suggest that using atorvastatin 80 mg will, in fact, decrease
cardiac events by a small additional amount compared with lower
intensity statin therapy. Whether that small benefit is worth a higher
cost and probably higher rate of side effects with more intensive
therapy depends on the patient's preferences.
If we're talking about someone without known CHD, whose only indication
for a statin is lipid lowering, I would not normally favor treatment
with high dose atorvastatin.
I don't agree with the implication that the difference between higher
intensity and lower intensity statin therapy is how quickly lipids will
return to normal. Statins aren't known to have some cumulative effect
that will continue to reduce lipid levels further and further over time.
--
David Rind
d...@xxxxxxxxxxxxxxxxxxxxx
Results of recent statin studies as compiled by Dr. Mary Enig, PhD*:
"Most doctors are convinced-and seek to convince their patients-that
the benefits of statin drugs far outweigh the side effects. They can
cite a number of studies in which statin use has lowered the number
of coronary deaths compared to controls. But as Dr. Ravnskov has
pointed out in his book The Cholesterol Myths,31 the results of the
major studies up to the year 2000-the 4S, WOSCOPS, CARE, AFCAPS and
LIPID studies-generally showed only small differences and these
differences were often statistically insignificant and independent of
the amount of cholesterol lowering achieved. In two studies, EXCEL,
and FACAPT/TexCAPS, more deaths occurred in the treatment group
compared to controls. Dr. Ravnskov's 1992 meta-analysis of 26
controlled cholesterol-lowering trials found an equal number of
cardiovascular deaths in the treatment and control groups and a
greater number of total deaths in the treatment groups.32 An analysis
of all the big controlled trials reported before 2000 found that long-
term use of statins for primary prevention of heart disase produced a
1 percent greater risk of death over 10 years compared to a placebo.33
Recently published studies do not provide any more justification for
the current campaign to put as many people as possible on statin
drugs.
Honolulu Hearth Program (2001)
This report, part of an ongoing study, looked at cholesterol lowering
in the elderly. Researchers compared changes in cholesterol
concentrations over 20 years with all-cause mortality.34 To quote:
"Our data accords with previous findings of increased mortality in
elderly people with low serum cholesterol, and show that long-term
persistence of low cholesterol concentration actually increases risk
of death. Thus, the earlier that patients start to have lower
cholesterol concentrations, the greater the risk of death. . . The
most striking findings were related to changes in cholesterol between
examination three (1971-74) and examination four (1991-93). There are
few studies that have cholesterol concentrations from the same
patients at both middle age and old age. Although our results lend
support to previous findings that low serum cholesterol imparts a
poor outlook when compared with higher concentrations of cholesterol
in elderly people, our data also suggest that those individuals with a
low serum cholesterol maintained over a 20-year period will have the
worst outlook for all-cause mortality [emphasis ours]."
MIRACL (2001)
The MIRACL study looked at the effects of a high dose of Lipitor on
3086 patients in the hospital after angina or nonfatal MI and
followed them for 16 weeks.35 According to the abstract: "For patients
with acute coronary syndrome, lipid-lowering therapy with
atorvastatin, 80 mg/day, reduced recurrent ischemic events in the
first 16 weeks, mostly recurrent symptomatic ischemia requiring
rehospitalization." What the abstract did not mention was that there
was no change in death rate compared to controls and no significant
change in re-infarction rate or need for resuscitation from cardiac
arrest. The only change was a significant drop in chest pain
requiring rehospitalization.
ALLHAT (2002)
ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial), the largest North American cholesterol-lowering
trial ever and the largest trial in the world using Lipitor, showed
mortality of the treatment group and controls after 3 or 6 years was
identical.36 Researchers used data from more than 10,000 participants
and followed them over a period of four years, comparing the use of a
statin drug to "usual care," namely maintaining proper body weight,
no smoking, regular exercise, etc., in treating subjects with
moderately high levels of LDL cholesterol. Of the 5170 subjects in the
group that received statin drugs, 28 percent lowered their LDL
cholesterol significantly. And of the 5185 usual-care subjects, about
11 percent had a similar drop in LDL. But both groups showed the same
rates of death, heart attack and heart disease.
Heart Protection Study (2002)
Carried out at Oxford University,37 this study received widespread
press coverage; researchers claimed "massive benefits" from
cholesterol-lowering,38 leading one commentator to predict that statin
drugs were "the new aspirin."39 But as Dr. Ravnskov points out,40 the
benefits were far from massive. Those who took simvastatin had an
87.1 percent survival rate after five years compared to an 85.4
percent survival rate for the controls and these results were
independent of the amount of cholesterol lowering. The authors of the
Heart Protection Study never published cumulative mortality data,
even though they received many requests to do so and even though they
received funding and carried out a study to look at cumulative data.
According to the authors, providing year-by-year mortality data would
be an "inappropriate" way of publishing their study results.41
PROSPER (2002)
PROSPER (Prospective Study of Pravastatin in the Elderly at Risk)
studied the effect of pravastatin compared to placebo in two older
populations of patients of which 56 percent were primary prevention
cases (no past or symptomatic cardiovascular disease) and 44 percent
were secondary prevention cases (past or symptomatic cardiovascular
disease).42 Pravastatin did not reduce total myocardial infarction or
total stroke in the primary prevention population but did so in the
secondary. However, measures of overall health impact in the combined
populations, total mortality and total serious adverse events were
unchanged by pravastatin as compared to the placebo and those in the
treatment group had increased cancer. In other words: not one life
saved.
J-LIT (2002)
Japanese Lipid Intervention Trial was a 6-year study of 47,294
patients treated with the same dose of simvastatin.43 Patients were
grouped by the amount of cholesterol lowering. Some patient had no
reduction in LDL levels, some had a moderate fall in LDL and some had
very large LDL reductions. The results: no correlation between the
amount of LDL lowering and death rate at five years. Those with LDL
cholesterol lower than 80 had a death rate of just over 3.5 at five
years; those whose LDL was over 200 had a death rate of just over 3.5
at five years.
Meta-Analysis (2003)
In a meta-analysis of 44 trials involving almost 10,000 patients, the
death rate was identical at 1 percent of patients in each of the
three groups-those taking atorvastatin (Lipitor), those taking other
statins and those taking nothing.44 Furthermore, 65 percent of those
on treatment versus 45 percent of the controls experienced an adverse
event. Researchers claimed that the incidence of adverse effects was
the same in all three groups, but 3 percent of the atorvastatin-
treated patients and 4 percent of those receiving other statins
withdrew due to treatment-associated adverse events, compared with 1
percent of patients on the placebo.
Statins and Plaque (2003)
A study published in the American Journal of Cardiology casts serious
doubts on the commonly held belief that lowering your LDL-
cholesterol, the so-called bad cholesterol, is the most effective way
to reduced arterial plaque.45 Researchers at Beth Israel Medical
Center in New York City examined the coronary plaque buildup in 182
subjects who took statin drugs to lower cholesterol levels. One group
of subjects used the drug aggressively (more than 80 mg per day)
while the balance of the subjects took less than 80 mg per day. Using
electron beam tomography, the researchers measured plaque in all of
the subjects before and after a study period of more than one year.
The subjects were generally successful in lowering their cholesterol,
but in the end there was no statistical difference in the two groups
in the progression of arterial calcified plaque. On average, subjects
in both groups showed a 9.2 percent increase in plaque buildup.
Statins and Women (2003)
No study has shown a significant reduction in mortality in women
treated with statins. The University of British Columbia Therapeutics
Initiative came to the same conclusion, with the finding that statins
offer no benefit to women for prevention of heart disease.46 Yet in
February of 2004, Circulation published an article in which more than
20 organizations endorsed cardiovascular disease prevention
guidelines for women with several mentions of "preferably a
statin."47
ASCOT-LLA (2003)
ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering
Arm) was designed to assess the benefits of atorvastatin (Lipitor)
versus a placebo in patients who had high blood pressure with average
or lower-than-average cholesterol concentrations and at least three
other cardiovascular risk factors.48 The trial was originally planned
for five years but was stopped after a median follow-up of 3.3 years
because of a significant reduction in cardiac events. Lipitor did
reduce total myocardial infarction and total stroke; however, total
mortality was not significantly reduced. In fact, women were worse off
with treatment. The trial report stated that total serious adverse
events "did not differ between patients assigned atorvastatin or
placebo," but did not supply the actual numbers of serious events.
Cholesterol Levels in Dialysis Patients (2004)
In a study of dialysis patients, those with higher cholesterol levels
had lower mortality than those with low cholesterol.49 Yet the authors
claimed that the "inverse association of total cholesterol level with
mortality in dialysis patients is likely due to the cholesterol-
lowering effect of systemic inflammation and malnutrition, not to a
protective effect of high cholesterol concentrations." Keeping an eye
on further funding opportunities, the authors concluded: "These
findings support treatment of hypercholesterolemia in this
population."
PROVE-IT (2004)
PROVE-IT (PRavastatin Or AtorVastatin Evaluation and Infection Study),
50 led by researchers at Harvard University Medical School, attracted
immense media attention. "Study of Two Cholesterol Drugs Finds One
Halts Heart Disease," was the headline in the New York Times.51 In an
editorial entitled "Extra-Low Cholesterol," the paper predicted that
"The findings could certainly presage a significant change in the way
heart disease patients are treated. It should also start a careful
evaluation of whether normally healthy people could benefit from a
sharp drug-induced reduction in their cholesterol levels."52
The Washington Post was even more effusive, with a headline "Striking
Benefits Found in Ultra-Low Cholesterol."53 "Heart patients who
achieved ultra-low cholesterol levels in one study were 16 percent
less likely to get sicker or to die than those who hit what are
usually considered optimal levels. The findings should prompt doctors
to give much higher doses of drugs known as statins to hundreds of
thousands of patients who already have severe heart problems, experts
said. In addition, it will probably encourage physicians to start
giving the medications to millions of healthy people who are not yet
on them, and to boost dosages for some of those already taking them to
lower their cholesterol even more, they said."
The study compared two statin drugs, Lipitor and Pravachol. Although
Bristol Myers-Squibb (BMS), makers of Pravachol, sponsored the study,
Lipitor (made by Pfizer) outperformed its rival Pravachol in lowering
LDL. The "striking benefit" was a 22 percent rate of death or further
adverse coronary events in the Lipitor patients compared to 26
percent in the Pravachol patients.
PROVE-IT investigators took 4162 patient who had been in the hospital
following an MI or unstable angina. Half got Pravachol and half got
Lipitor. Those taking Lipitor had the greatest reduction of LDL-
cholesterol-LDL in the Pravachol group was 95, in the Lipitor group
it was 62-a 32 percent greater reduction in LDL levels and a 16
percent reduction in all-cause mortality. But that 16 percent was a
reduction in relative risk. As pointed out by Red Flags Daily
columnist Dr. Malcolm Kendrick, the absolute reduction in the rate of
the death rate of those taking Lipitor rather than Pravachol, was one
percent, a decrease from 3.2 percent to 2.2 percent over 2 years.54
Or, to put it another way, a 0.5 percent absolute risk reduction per
year-these were the figures that launched the massive campaign for
cholesterol-lowering in people with no risk factors for heart
disease, not even high cholesterol.
And the study was seriously flawed with what Kendrick calls "the two-
variables conundrum." "It is true that those with the greatest LDL
lowering were protected against death. However, . . . those who were
protected not only had a greater degree of LDL lowering, they were
also on a different drug! which is rather important, yet seems to
have been swept aside on a wave of hype. If you really want to prove
that the more you lower the LDL level, the greater the protection,
then you must use the same drug. This achieves the absolutely
critical requirement of any scientific experiment, which is to remove
all possible uncontrolled variables. . . As this study presently
stands, because they used different drugs, anyone can make the case
that the benefits seen in the patients on atorvastatin [Lipitor] had
nothing to do with greater LDL lowering; they were purely due to the
direct drug effects of atorvastatin." Kendrick notes that the
carefully constructed J-LIT study, published 2 years earlier, found
no correlation whatsoever between the amount of LDL lowering and
death rate. This study had ten times as many patients, lasted almost
three times as long and used the same drug at the same dose in all
patients. Not surprisingly, J-LIT attracted virtually no media
attention.
PROVE-IT did not look at side effects but Dr. Andrew G. Bodnar,
senior vice president for strategy and medical and external affairs
at Bristol Meyer Squibb, makers of the losing statin, indicated that
liver enzymes were elevated in 3.3 percent of the Lipitor group but
only in 1.1 percent of the Pravachol group, noting that when liver
enzyme levels rise, patients must be advised to stop taking the drug
or reduce the dose.55 And withdrawal rates were very high: thirty-
three percent of patients discontinued Pravachol and 30 percent
discontinued Lipitor after two years due to adverse events or other
reasons.56
REVERSAL (2004)
In a similar study, carried out at the Cleveland Clinic, patients
were given either Lipitor or Pravachol. Those receiving Lipitor
achieved much lower LDL-cholesterol levels and a reversal in "the
progression of coronary plaque aggregation."57 Those who took Lipitor
had plaque reduced by 0.4 percent over 18 months, based on
intravascular ultrasound (not the more accurate tool of electron beam
tomography); Dr. Eric Topol of the Cleveland Clinic claimed these
decidedly unspectacular results "Herald a shake-up in the field of
cardiovascular prevention.. . . 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."58 Not surprisingly, an article in The
Wall Street Journal noted "Lipitor Prescriptions Surge in Wake of Big
Study."59
But as Dr. Ravnskov points out, the investigators looked at change in
atheroma volume, not the change in lumen area, "a more important
parameter because it determines the amount of blood that can be
delivered to the myocardium. Change of atheroma volume cannot be
translated to clinical events because adaptive mechansims try to
maintain a normal lumen area during early atherogenesis."60
REFERENCES
31. Uffe Ravnskov, MD, PhD. The Cholesterol Myths. NewTrends
Publishing, 2000.
32. Ravnskov U. BMJ. 1992;305:15-19.
33. Jackson PR. Br J Clin Pharmacol 2001;52:439-46.
34. Schatz IJ and others. Lancet 2001 Aug 4;358:351-355.
35. Schwartz GG and others. J Am Med Assoc. 2001;285:1711-8.
36. The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. JAMA 2002;288:2998-3007.
37. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
38. Medical Research Council/British Heart Foundation Heart
Protection Study.Press release. Life-saver: World's largest
cholesterol-lowering trial reveals massive benefits for high-risk
patients. Available at www.ctsu.ox.ac.uk/~hps/pr.shtml.
39. Kmietowicz A. BMJ 2001;323:1145
40. Ravnskov U. BMJ 2002;324:789
41. Email communication, Eddie Vos, February 13, 2004 and posted at
www.health-heart.org/comments.htm#PetoCollins.
42. Shepherd J and others. Lancet 2002;360:1623-1630.
43. Matsuzaki M and others. Circ J. 2002 Dec;66(12):1087-95.
44. Hecht HS, Harmon SM. Am J Cardiol 2003; 92:670-676
45. Hecht HS and others. Am J Cardiol 2003;92:334-336
46. Jenkins AJ. BMJ 2003 Oct 18;327(7420):933.
47. Circulation, 2004 Feb 17;109(6):714-21.
48. Sever PS and others. Lancet 2003;361:1149-1158.
49. Liu Y and others. JAMA 2004;291:451-459.
50. Cannon CP and others. N Engl J Med 2004 Apr 8;350(15):1495-504.
Epub 2004 Mar 08.
51. Gina Kolata. Study of Two Cholesterol Drugs Finds One Halts Heart
Disease. The New York Times, November 13, 2003.
52. Extra-Low Cholesterol, The New York Times, March 10, 2003
53. Rob Stein. Striking Benefits Found in Ultra-Low Cholesterol, The
Washington Post, March 9, 2004
54. Dr. Malcolm Kendrick. PROVE IT- PROVE WHAT?
http://www.redflagsweekly.com/applications/ui/login.php?Next=/kendrick/2004_mar10.php&e=4
55. Health Sciences Institute e-alert, www.hsibaltimore.com, March
11, 2004
56. Email communication, Joel Kauffman, April 15, 2004.
57. Nissen SE and others. JAMA 2004 Mar 3;291(9):1071-80.
58. Dr. Malcolm Kendrick. PROVE IT- PROVE WHAT?
http://www.redflagsweekly.com/applications/ui/login.php?Next=/kendrick/2004_mar10.php&e=4
59. Scott Hensley. The Statin Dilemma: How Sluggish Sales Hurt
Merck, Pfizer. The Wall Street Journal, July 25, 2003.
60. Ravnskov, U. Unpublished letter. ravnskov@xxxxxxxx "
*Dr. Mary G. Enig, a nutritionist/biochemist of international renown
for her research on the nutritional aspects of fats and oils, is a
consultant, clinician, and the Director of the Nutritional Sciences
Division of Enig Associates, Inc., Silver Spring, Maryland. Dr. Enig,
a consultant on nutrition to individuals, industry, and state and
federal governments, is a licensed practitioner in Maryland and the
District of Columbia. She has served as a Contributing Editor of the
scientific journal Clinical Nutrition and a Consulting Editor of the
Journal of the American College of Nutrition.
Dr. Enig has authored numerous journal publications, mainly on fats
and oils research and nutrient/drug interactions, and is a well-known
invited lecturer at scientific meetings and a popular interviewee on
TV and radio shows about nutrition. She was an early and articulate
critic of the use of trans fatty acids and advocated their inclusion
in nutritional labeling; the scientific mainstream is now challenging
the food product industry's use of trans-containing partially
hydrogenated vegetable oils. She received her Ph.D. in Nutritional
Sciences from the University of Maryland, College Park, and is a
Fellow of The American College of Nutrition, a member of The American
Society for Nutritional Sciences, and President of the Maryland
Nutritionists Association
.
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