Statin Drugs Revisited by Jeffrey Dach MD
This article takes a critical look at statin anti-cholesterol drugs.
These are block busters worth billions to the drug manufacturers.
This article asks the hard questions. Do statin drugs work? Who do
they work for ? and who do they harm? Who should be taking them, and
who should not be taking them? Examples of Statin Drugs are Lipitor,
Zocor, Simvastatin, Pravachol, Crestor, Mevacor, etc. These drugs
reduce the production of cholesterol by the liver by inhibiting an
enzyme called HMG-CoA. Since it is generally believed that cholesterol
causes heart disease, statin drug reduction of cholesterol is a
mainstream medical treatment for prevention of heart disease.
Anti-Inflammatory Effect
After many decades of study and clinical trials, it has become clear
that the benefit of statin drugs (if there is any) is probably not due
to reduction in cholesterol, rather it is due to an
anti-inflammatory effect of the drug.(
link)
Reducing CoQ-10
Coincidentally, statin drugs also inhibit the production of an
important mitochondrial cofactor called Co-Q10, accounting for adverse
effects as mitochondrial toxins. In addition, a low serum cholesterol
level is a health risk for many reasons. Cholesterol is an important
molecule in the body, and reducing cholesterol to low levels is
associated with increased mortality and
adverse effects on health. (27)
Asking A Few Questions
In this article we will revisit anti-cholesterol statin drugs while asking the following questions:
1) What is the efficacy for statin drugs in primary prevention of heart disease (in normal healthy people)?
2) What is the efficacy of statin drugs in secondary prevention (patients with known underlying heart disease)?
3) Which subgroups benefit from statin drugs, and which subgroups of the population are harmed by statin drugs?
The Elderly – Low Serum Cholesterol Predicts Increased Mortality
First, let’s take a look at the medical practice of prescribing
statin anti-cholesterol drugs for the elderly. Contrary to current
dogma, higher cholesterol levels in the elderly are not a heath risk.
Studies show that higher cholesterol in the elderly is associated with
increased survival, while lower total serum cholesterol values in the
elderly are a robust predictor of
increased mortality. (1, 4,5)
The Prosper Study – Statins for the Elderly
When statin drugs are given to the elderly to reduce cholesterol
values as was done in the PROSPER study, there was no mortality benefit
for either primary or secondary prevention of heart disease. (1,6,7)
True, there was a reduction in cardiac mortality of about 20% in the
secondary prevention group in the Prosper study, however, this was
counterbalanced by an increase in cancer mortality, yielding no over-all
mortality benefit in the final analysis.
Women- No Mortality Benefit from Statins
Perhaps the best summary of the results of three decades of statin
drug studies in women can be found in the Judith Walsh MD report in JAMA
May 2004. (8) Again, Dr Walsh found that statin drug treatment to
reduce cholesterol in women provided
no mortality benefit
in both primary and secondary prevention of heart disease. As we found
in the PROSPER study for the elderly, statin drug use in women (with
known heart disease) resulted in a reduction in mortality from heart
disease, and a reduction in heart attacks in this secondary prevention
group, however, this was offset by additional deaths from cancer and
other mortality which yielded no over-all mortality benefit in the final
analysis. (8)
Men and Women – Statin Drugs for Primary Prevention-
Dr Ray in the Archives of Internal Medicine
Perhaps the best single review of primary prevention of heart disease
with statin drugs comes from Dr Ray in the 2010 Archives of Internal
Medicine. (9,10) Dr. Ray reviewed 11 randomized Statin Drug trials with
65,000 participants finding NO ALL-Cause Mortality Benefit from statin
drug treatment to reduce cholesterol values in primary prevention of
heart disease (people without known heart disease).(9,10)
Dr Stephen Sinatra- Restrict Statin Drugs to Men with Known Heart Disease (11)
Now we can summarize the above information. In Women and the
Elderly, Statin drugs offer no mortality benefit for primary or
secondary prevention of heart disease.
In addition, Statin drugs offer no mortality benefit for men in
primary prevention of heart disease (men with no known heart disease).
This leaves us with the remaining group in which statin drugs HAVE
BEEN SHOWN to provide a mortality benefit. This group is males with
known heart disease, also called secondary prevention.
And now, we can understand the rationale for Dr Stephen Sinatra’s
position on statin drugs announced in his newsletter.(11) Dr. Sinatra
says that statin drugs should be prescribed only to middle aged males
with known heart disease. For other groups, Dr Sinatra considers statin
drugs unnecessary and potentially harmful. (11)
Secondary Prevention of Heart Disease in Males
Considering the media and marketing hype over statin drugs, one would
think there must be something to it, so let’s take a look at the statin
drug studies in the best case scenario, middle aged men with known
heart disease. This is the group with proven mortality benefit and
these studies were submitted for FDA approval for this class of drugs.
Let’s take a closer look at the data from two of the most representative
secondary prevention studies with statin drugs, the 4S (12,13) and the
LIPID Studies (14).
4S Trial with Simvastatin in Scandinavia (12,13) – 0.6% per year
Here is a quick recap of the 4S-Trial data.
The 4S trial was done on 4444 patients who had known heart disease,
randomized to simvastatin or placebo, and followed for 5.5 years. At
the end of the follow up, they reported 182 deaths in the statin drug
group (8.2 %) and 256 deaths in the placebo group (11.5% ). This
provided an absolute mortality benefit of 3.3% over 5.5 years, or 0.6%
per year. (12,13) The 6-year probabilities of survival for placebo was
88.5 % and for simvastatin was 91.8%, a difference of 3.3%.
LIPID Pravastatin Study (14) – 0.5% per year
Here is a quick recap of the LIPID Trial data.
9,000 patients with unstable angina and history of myocardial
infarction were randomized to either placebo or Pravastatin and followed
for 6.1 years.(14)
The statin group had 11% mortality and the placebo group had 14.1 %
mortality over 6.1 years. This is a 3.1% mortality benefit over 6.1
years or 0.5% per year. After 6 years probability of survival in the
placebo group is 85.9% and in the Statin drug group is 89%, a difference
of 3.1 %. (14)
Absolute Mortality Benefit of 0.5% per year in Secondary Prevention
So, as you can see from the above, the absolute mortality benefit in
the best case scenario, in secondary prevention trials, is only 0.5% –
0.6% per year. This benefit is underwhelming, and actually quite
shocking that it is such a minimal benefit when the drug company
marketing would suggest much larger benefits.
So in conclusion, Statin drugs do have a mortality benefit, however,
this is restricted to men with known heart disease amounting to about
0.5% per year reduction in mortality compared to a placebo. This
benefit is so miniscule that one wonders why statin drugs are
recommended at all, considering their severe adverse side effects with
memory loss, neuropathy, muscle pain and weakness. For women, the
elderly, and all men without underlying heart disease, Dr Sinatra
reminds us that statin drugs are unnecessary and potentially harmful.
Do Statin Drugs Prevent Progression or Reverse Atherosclerotic Plaque?
This question comes up form time to time, and is an important one,
since people with heart disease are interested in interventions which
can prevent progression or reverse atherosclerotic plaque formation in
the coronary arteries.
The coronary calcium score studies (16), Hi-Speed CAT scan coronary
angiogram studies, and intravascular ultrasound studies (15) reveal
in-vivo imaging of atherosclerotic plaque over time and can provide
these answers.
Some of the calcium score studies, such as Budoff’s (26), showed
reduced progression or even regression of calcium score, suggestion
reduction in atherosclerotic plaque with statin drug treatment.(15-26)
However, some of the calcium score studies were disappointing,
showing no improvement in calcium score with statin treatment. This was
thought to be due to reduction in soft plaque with no reduction in the
calcific plaque. (15-26)
Can Statin Drugs Reverse Plaque ?
The totality of all the imaging studies provides fairly strong
evidence that statin drug treatment is capable of halting progression,
or even regression of atherosclerotic plaque in various locations in the
arterial tree. However, the problem arises as to what happens to the
rest of the patient. For example, the Calcium score study done with the
banned statin drug, Baychol, showed striking regression of
atherosclerotic plaque. (16) However, the drug was banned after killing
fifty people. This brings to mind the old sarcastic medical comment,
“The operation was a success but the patient died.”
What is the Price ?
So the final answer is that, yes, intervention with statin drugs can
halt progression or reverse atherosclerotic plaque. However, the price
in adverse effects is great, with non-cardiac mortality offsetting
reduction in cardiac mortality, explaining the lack of all-cause
mortality benefit in primary prevention studies, and for studies in
women, and in studies in the elderly (PROSPER). After all, statin drugs
are mitochondrial toxins, and a reduction in serum cholesterol is an
unhealthy intervention which causes disruption of normal cell
physiology. Low serum cholesterol is associated with increased
mortality from NON-cardiac causes. Dr Judith Walsh reviews these
problems and concludes that it is time to change direction in health
policy. (27)
What are the other interventions to halt progression or reverse heart disease?
This brings us inexorably to the question of what are the alternatives to statin drugs?
Hormone Levels
There is strong supporting evidence that optimization of hormone
levels is a valuable intervention for prevention of heart disease
associated with minimal adverse effects. These include thyroid hormone,
testosterone, estrogen and vitamin D (which is also a steroidal
hormone).
HUNT Study – Thyroid Function and Heart Disease
The
Hunt Study
is strong evidence optimizing thyroid function to reduce mortality from
heart disease. People (Men and Women) in the upper third of thyroid
function (lower third of TSH range) had 70% reduction in mortality from
heart disease.(28,29) (
LINK)
Testosterone Prevents Heart Disease
The latest study on Testosterone reducing mortality from heart disease comes from an
abstract presented at the 2011 Society for Endocrinology meeting.(30,31) (
LINK)
The authors found a 2% per year annual reduction in mortality with
testosterone treatment in a group of diabetic men with low
testosterone. Compare this 2% reduction with the 0.6 % annual mortality
reduction in best case scenario statin trials of secondary
prevention. Testosterone is a far better treatment option with none of
the adverse effects of statin drugs.
Estrogen in Menopausal Women Prevents Heart Disease and Reduces All Cause Mortality (32-36)
The 11 year follow up the the second arm of the WHI (Women’s Health Initiative Data was published in
JAMA and
Lancet Oncology
(32-36) showing that the Estrogen Treatment in the 50-59 year age group
had a 40 % reduction in all-cause mortality, a 46% reduction in heart
attacks, and a 23 % reduction in breast cancer.(32-36). Here is the
DATA PAGE for the 2011 JAMA report on the WHI second arm.
This study showed a reduction in heart disease and all cause
mortality in women, a result exceeding any previous statin drug trials
in women. This is strong evidence that estrogen replacement in
menopausal women is a far more effective and healthier intervention than
is the use of a statin drug in women.
Diet and Lifestyle Modification
Coronary heart disease is a diet and lifestyle disease. Yes, of
course, there are underlying genetic predispositions in some patients,
however, diet and lifestyle represents by far the largest etiologic
factor which can be modified with striking benefits.
This is further discussed in my previous articles found here:
Track Your Plaque Program – William Davis MD
Track Your Plaque -How to Reverse Heart Disease with the Coronary Calcium Score, the William Davis MD Program
Track Your Plaque, Heart Disease Prevention Part Two
Preventing and Reversing Heart Disease, Part Three
Thyroid Prevents Heart Disease -Hunt Study
Low thyroid is a high risk factor for heart disease.
Linus Pauling Protocol
Heart Disease, Ascorbate, Lysine and Linus Pauling
The Linus Pauling Protocol for prevention of heart disease.
A Choirboy for Cholesterol Turns Disbeliever
Reversing Heart Disease without Drugs
More articles with related interest:
Cholesterol Lowering Statin Drugs for Women, Just Say No
Women don’t benefit from statin drugs and here’s why.
A Choirboy for Cholesterol Turns Disbeliever
Steven Sinatra MD discusses why he turned against statin drugs.
Cardiac Stent, Angioplasty, Bypass
29 studies show that procedures have No Benefit when compared to conventional heart drug treatments.
Cholesterol Lowering Drugs for the Elderly, a Very Bad Idea
Elderly have improved survival with higher vholesterol, not lower.
Lipitor and The Dracula of Modern Technology
A closer look at the Jarvik ads for Lipitor.
Jeffrey Dach MD
Links and References
1)
www.cmaj.ca/content/173/10/1207.2.full
Letters Questioning the benefits of statins
Eddie Vos*, Colin P. Rose† + Author Affiliations *Sutton, Que.; †Cardiologist, McGill University, Montréal, Que.
The assessment by Douglas Manuel and associates1 of the 2003 Canadian
dyslipidemia guidelines2 is welcome, but they overlooked the all-cause
mortality issue, where statins have essentially failed to deliver.1
There are no statin trials with even the slightest hint of a mortality benefit in women,3,4,5 and women should be told so.
Likewise, evidence in patients over 70 years old shows no mortality
benefit of statin therapy: in the PROSPER trial there were 28 fewer
deaths from coronary artery disease in patients who received pravastatin
versus placebo, offset by 24 more cancer deaths.6
The failure of statins to decrease all-cause mortality is possibly
best illustrated by atorvastatin: while both the ASCOT7 and TNT8 trials
found that atorvastatin therapy decreased the risk of cardiovascular
events, in the ASCOT trial (placebo v. 10 mg atorvastatin daily) the
all-cause mortality curves effectively touched at mean study end (3.3
years) and in the TNT trial (10 v. 80 mg of atorvastatin daily) there
were 26 fewer deaths from coronary artery disease in patients taking the
higher dose offset by 31 more noncardiovascular deaths at median study
end (4.9 years).
Incidentally, the ASCOT trial failed to find a cardiac benefit of
statin therapy in women and patients with diabetes. The Web site of the
ALLHAT study says it best:9 “trials [primarily in middle-aged men]
demonstrating a reduction in [coronary artery disease] from cholesterol
lowering have not demonstrated a net reduction in all-cause mortality.”
What is the point of decreasing the number of “events” without
decreasing overall mortality, when the harm caused by the side effects
of statin therapy is factored in? The failure of statins to reduce
all-cause mortality clearly supports the call for more effective
approaches. Guidelines should reflect this finding, certainly in their
recommendations for women and probably in those for most men too.
====================================================
Statins Useless for Primary Prevention
2)
archinte.ama-assn.org/cgi/content/full/171/17/1594
Archives of Internal Medicine Vol. 171 No. 17, September 26, 2011
To Make the Case—Evidence Is Required Comment on “Making the Case for
Selective Use of Statins in the Primary Prevention Setting” Rita F.
Redberg, MD, MSc, Editor; Mitchell Katz, MD; Deborah Grady, MD, MPH Arch
Intern Med. 2011;171(17):1594.
Minder et al disagree that statins for primary prevention are an
example of a widely used medication with no known benefit and definite
risks. Although they concede that the evidence that statins prolong
survival is “less than robust,” they state that such evidence cannot be
expected from trials in which patients were only treated for a few
years. To support their belief in statin use for primary prevention they
cite a meta-analysis (Brugts et al1) that includes data from studies of
both primary and secondary prevention, where most of the benefit
occurred in the studies of secondary prevention. Importantly, Minder et
al do not acknowledge the commonly reported adverse effects associated
with statins, including memory loss, muscle pains, weakness, and liver
function abnormalities. For a medicine to be recommended to healthy
patients for a lifetime of use, there should be robust evidence that
this regime will reduce suffering or extend life, and evidence that the
benefit outweighs adverse effects. Until there is such data for statins
for primary prevention, we will continue to classify it as an
intervention without known benefit, but with definite risks, in our Less
Is More series.
==============================
3)
www.ncbi.nlm.nih.gov/pubmed/19263395
Martinez-Carpio PA, et al.
Relation between cholesterol levels and neuropsychiatric disorders.
Rev Neurol 2009;48(5):261-4 Rev Neurol. 2009 Mar 1-15;48(5):261-4.
[Relation between cholesterol levels and neuropsychiatric disorders].
[Article in Spanish] Martínez-Carpio PA, Barba J, Bedoya-Del Campillo A.
Source Centro Penitenciario de Jóvenes de Barcelona, Generalitat de
Catalunya, Sant Joan de Déu, Barcelona, España. pmc@investilaser.com
Abstract
INTRODUCTION: A recent survey raised doubts about most of the
associations between hypocholesterolemia and neuropsychiatric diseases.
Nevertheless, there is scientific evidence (some very recent) that
demonstrates a link between possible brain disorders and reduced levels
of cholesterol.
AIM: To conduct a systematic study of the literature that addresses
the relation between low cholesterol levels in serum and
neuropsychiatric disorders.
DEVELOPMENT: Relevant papers were identified by means of a systematic
search and selection of the literature on Medline (August 2008). The
selected papers were reviewed using statistical analysis and
critical-deductive reasoning.
CONCLUSIONS: It is shown that low cholesterol levels in serum are
associated and related to different neuropsychiatric disorders. Lowered
cholesterol levels seem likely to be linked to higher rates of early
death, suicide, aggressive and violent behaviour, personality disorders,
and possibly depression, dementia and penal confinement among young
males. Further studies are needed to confirm the evidence currently
available and to relate more accurate diagnoses with
hypocholesterolemia.
——————————————————————
Elderly
4)
Krumholz HM, et al.
http://www.ncbi.nlm.nih.gov/pubmed/7772105
Lack of association between cholesterol and coronary heart disease
mortality and morbidity and all-cause mortality in persons older than 70
years. JAMA 1994;272(17):1335-40
5)
http://www.ncbi.nlm.nih.gov/pubmed/11502313
Schatz IJ, et al.
Cholesterol and all-cause mortality in elderly people from the Honolulu
Heart Program: a cohort study. Lancet 2001;358(9279):351-5. the
association between cholesterol levels and overall risk of death was
assessed over 20 years in individuals aged 71-93 at the start of the
study [2]. Those with the highest cholesterol levels were found to be 35
per cent less likely to die than individuals with the lowest levels.
Those with persistently low levels of cholesterol were found to be at
significantly increased risk of death. The authors concluded that their
‘data cast doubt on the scientific justification for lowering
cholesterol to very low concentrations… in elderly people. women
6)
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)11600-X/abstract
Pravastatin in elderly individuals at risk of vascular disease
(PROSPER): a randomised controlled trial by Prof James Shepherd MD et
al. on behalf of the PROSPER study group
Elderly – Provastatin Study
7)
healthandpharma.awardspace.com/Week%204%20Readings/Mangin%20Preventitive%20Health%20Care.pdf
Preventive health care in elderly people needs rethinking
BMJ 2007;335:285 Dee Mangin senior lecturer in general practice,
Christ church School of Medicine, University of Otago, Christ church,
New Zealand
The largest study in this group is the pravastatin in elderly
individuals at risk of vascular disease (PROSPER) trial. In this trial
more than 5000 participants, aged 70-82 years, were followed up for an
average of 3.2 years.4 Pravastatin had a clear but small effect on
mortality and morbidity from cardiovascular disease using the primary
composite end point (absolute risk reduction 2.1%, number needed to
treat 48; figure). These data are used to underpin the study conclusions
and those of subsequent guidelines that vascular prevention strategies
in middle aged people should also be applied to elderly people.
However, examination of all mortality and morbidity data is revealing.4
Pravastatin showed no benefit over placebo for any outcome in elderly
women and despite a change in composite cardiovascular outcomes, all
cause mortality stayed the same (hazard ratio 0.97, 95% confidence
interval 0.83 to 1.14; figure), inferring that mortality and morbidity
from other causes must have increased. Rates of cancer diagnosis and
death were higher in the treatment group than in the placebo group. The
difference was significant for a new diagnosis of cancer (1.25, 1.04 to
1.51; absolute risk increase 1.7%, number needed to treat 59; figure)
and almost significant for mortality from cancer (1.28, 0.97 to 1.68).
Preventive use of statins shows no overall benefit in elderly people
as cardiovascular mortality and morbidity are replaced by cancer A more
sophisticated model is needed to assess the benefits and harms of
preventive treatment in elderly people
—————————–
Statin Drugs – No Mortality Benefit for women
8)
http://www.ncbi.nlm.nih.gov/pubmed/15138247
JAMA. 2004 May 12;291(18):2243-52. Drug treatment of hyperlipidemia in women.
Walsh JM, Pignone M. Division of General Internal Medicine and
Department of Epidemiology and Biostatistics, University of California,
San Francisco, USA.
Primary Prevention of Heart Disease With Statins
9)
http://archinte.ama-assn.org/cgi/content/short/170/12/1024
Statins and All-Cause Mortality in High-Risk Primary Prevention
A Meta-analysis of 11 Randomized Controlled Trials Involving 65 229 Participants
Kausik K. Ray, MD, MPhil, FACC, FESC; Sreenivasa Rao Kondapally
Seshasai, MD, MPhil; Sebhat Erqou, MD, MPhil, PhD; Peter Sever, PhD,
FRCP, FESC; J. Wouter Jukema, MD, PhD; Ian Ford, PhD; Naveed Sattar,
FRCPath
Arch Intern Med. 2010;170(12):1024-1031.
Data were combined from 11 studies and effect estimates were pooled
using a random-effects model meta-analysis, with heterogeneity assessed
with the I2 statistic. Data were available on 65 229 participants
followed for approximately 244 000 person-years, during which 2793
deaths occurred.
The use of statins in this high-risk primary prevention setting was
not associated with a statistically significant reduction (risk ratio,
0.91; 95% confidence interval, 0.83-1.01) in the risk of all-cause
mortality.
Conclusion This literature-based meta-analysis did not find evidence
for the benefit of statin therapy on all-cause mortality in a high-risk
primary prevention set-up.
10)
www.ti.ubc.ca/pages/letter48.htm
Therapeutics Letter, issue 48, April – June 2003
Do Statins have a Role in Primary Prevention? Therapeutics Initiative 2176 Health Sciences Mall Vancouver, BC, Canada
Stephen Sinatra MD
11)
blog.drsinatra.com/blog/heart-health-nutrition/new-fda-statin-warning
The FDA Finally Acknowledged Statins Can Cause Diabetes and Memory Loss Wednesday, February 29, 2012 by Stephen Sinatra
So, while I do continue to recommend statins for middle-aged men with
known coronary artery disease, for most people I feel they’re
unnecessary and potentially harmful.
—————————————————-
4S Study Seconday Prevention
12)
http://www.ncbi.nlm.nih.gov/pubmed/7572690
Am J Cardiol. 1995 Sep 28;76(9):64C-68C.
Reducing the risk of coronary events: evidence from the Scandinavian
Simvastatin Survival Study (4S). Kjekshus J, Pedersen TR. National
Hospital, Department of Medicine, Oslo, Norway.
The Scandinavian Simvastatin Survival Study (4S) was designed to
evaluate the effects of cholesterol reduction with simvastatin on
mortality and morbidity in patients with coronary artery disease (CAD). A
total of 4,444 patients with angina pectoris or previous myocardial
infarction and serum cholesterol levels of 213-310 mg/dl (5.5-8.0
mmol/liter) while treated with a lipid-lowering diet were randomly
assigned to double-blind treatment with simvastatin or placebo. Over the
5.4 years of median follow-up, simvastatin produced changes in total
cholesterol, low density lipoprotein (LDL) cholesterol, and high density
lipoprotein (HDL) cholesterol of -25%, -35%, and +8%, respectively,
with minimal adverse effects.
A total of 256 patients (12%) in the placebo group died compared with
182 (8%) in the simvastatin group, a risk reduction of 30% (p = 0.0003)
attributable to a 42% reduction in the risk of coronary death.
Noncardiovascular causes accounted for 49 and 46 deaths in the
placebo and simvastatin groups, respectively. Major coronary events were
experienced by 622 patients (28%) in the placebo group and 431 patients
(19%) in the simvastatin group, corresponding to a risk reduction of
34% (p < 0.00001).
13)
http://www.ncbi.nlm.nih.gov/pubmed/9576425
Circulation. 1998 Apr 21;97(15):1453-60.
Lipoprotein changes and reduction in the incidence of major coronary
heart disease events in the Scandinavian Simvastatin Survival Study (4S)
Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K,
Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyörälä K, Miettinen T,
Christophersen B, Tobert JA, Musliner TA, Cook TJ. Aker Hospital, Oslo,
Norway.
14) LIPID STUDY
http://www.nejm.org/doi/full/10.1056/NEJM199811053391902
Prevention of Cardiovascular Events and Death with Pravastatin in
Patients with Coronary Heart Disease and a Broad Range of Initial
Cholesterol Levels
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
N Engl J Med 1998; 339:1349-1357November 5, 1998
——————–
15)
http://cdn.intechweb.org/pdfs/18255.pdf
Ultrasound Imaging – Medical Applications, ISBN: 978-953-307-279-1
Atherosclerotic Plaque Regression and Arterial Reverse Remodelling in
Carotid and Femoral Arteries by Statin Use in Primary Prevention
Setting: Ultrasound Findings
By Cesare Rusconi, Riccardo Raddino, Eleftheria Trichaki and Livio Dei Cas
Baychol Intensive Statin Therapy reduces CAC
16)
www.ncbi.nlm.nih.gov/pubmed/12196332 circ.ahajournals.org/content/106/9/1077.long Circulation. 2002 Aug 27;106(9):1077-82.
Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation.
Achenbach S, Ropers D, Pohle K, Leber A, Thilo C, Knez A, Menendez T,
Maeffert R, Kusus M, Regenfus M, Bickel A, Haberl R, Steinbeck G,
Moshage W, Daniel WG. Source Department of Internal Medicine II,
University of Erlangen-Nürnberg, Germany.
Abstract BACKGROUND:
Coronary calcification measured by fast computed tomography techniques
is a surrogate marker of coronary atherosclerotic plaque burden. In a
cohort study, we prospectively investigated whether lipid-lowering
therapy with a cholesterol synthesis enzyme inhibitor reduces the
progression of coronary calcification.
METHODS AND RESULTS: In 66 patients with coronary calcifications in
electron beam tomography (EBT), LDL cholesterol >130 mg/dL, and no
lipid-lowering treatment, the EBT scan was repeated after a mean
interval of 14 months and treatment with cerivastatin BAYCHOL was
initiated (0.3 mg/d).
After 12 months of treatment, a third EBT scan was performed.
Coronary calcifications were quantified using a volumetric score.
Cerivastatin therapy lowered the mean LDL cholesterol level from
164+/-30 to 107+/-21 mg/dL. The median calcified volume was 155 mm3
(range, 15 to 1849) at baseline, 201 mm3 (19 to 2486) after 14 months
without treatment, and 203 mm3 (15 to 2569) after 12 months of
cerivastatin treatment. The median annualized absolute increase in
coronary calcium was 25 mm3 during the untreated versus 11 mm3 during
the treatment period (P=0.01).
The median annual relative increase in coronary calcium was 25%
during the untreated versus 8.8% during the treatment period
(P<0.0001).
In 32 patients with an LDL cholesterol level <100 mg/dL under
treatment, the median relative change was 27% during the untreated
versus -3.4% during the treatment period (P=0.0001).
CONCLUSIONS: Treatment with the cholesterol synthesis enzyme
inhibitor cerivastatin (baycol) significantly reduces coronary calcium
progression in patients with LDL cholesterol >130 mg/dL.
Note: Baycol was withdrawn in 2001 because of fatal rabdomyalysis.
—————————————
Statins Reduce CAC if LDL less than 120, other wise 50% progression
17)
www.ncbi.nlm.nih.gov/pubmed/9869668
N Engl J Med. 1998 Dec 31;339(27):1972-8.
Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.
Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Source
Electron Beam Tomography Research Foundation, Hendersonville, TN 37075,
USA.
We conducted a retrospective study of 149 patients (61 percent men
and 39 percent women; age range, 32 to 75 years) with no history of
coronary artery disease who were referred by their primary care
physicians for screening electron-beam CT. All patients underwent
base-line scanning and follow-up assessment after a minimum of 12 months
(range, 12 to 15), and a volumetric calcium score was calculated as an
estimate of the total burden of plaque.
Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors was begun at the discretion of the referring
physician. Serial measurements of low-density lipoprotein (LDL)
cholesterol were obtained, and the change in the calcium-volume score
was correlated with average LDL cholesterol levels.
RESULTS: One hundred five patients (70 percent) received treatment
with HMG-CoA reductase inhibitors, and 44 patients (30 percent) did not.
At follow-up, a net reduction in the calcium-volume score was
observed only in the 65 treated patients whose final LDL cholesterol
levels were less than 120 mg per deciliter (3.10 mmol per liter) (mean
[+/-SD] change in the score, -7+/-23 percent; P=0.01).
Untreated patients had an average LDL cholesterol level of at least
120 mg per deciliter and at the time of follow-up had a significant net
increase in mean calcium-volume score (mean change, +52+/-36 percent;
P<0.001).
The 40 treated patients who had average LDL cholesterol levels of at
least 120 mg per deciliter had a measurable increase in mean
calcium-volume score (25+/-22 percent, P<0.001), although it was
smaller than the increase in the untreated patients.
CONCLUSIONS: The extent to which the volume of atherosclerotic plaque
decreased, stabilized, or increased was directly related to treatment
with HMG-CoA reductase inhibitors and the resulting serum LDL
cholesterol levels. These changes can be determined noninvasively by
electron-beam CT and quantified with use of a calcium-volume score.
——————————————————–
Primary Prevention- no difference in progression with more aggressive lipid lowering
18)
www.ncbi.nlm.nih.gov/pubmed/12888149
Am J Cardiol. 2003 Aug 1;92(3):334-6.
Relation of aggressiveness of lipid-lowering treatment to changes in
calcified plaque burden by electron beam tomography. Hecht HS, Harman
SM. Source Beth Israel Medical Center, New York,
The comparative effects of more versus less aggressive low-density
lipoprotein (LDL) cholesterol lowering (to 80 mg/dl) on calcified
coronary plaque progression by electron beam tomography were evaluated
in 182 consecutive asymptomatic patients after 1.2 years of treatment
with statins alone or in combination with niacin.
Despite the greater improvement in lipids in the 80 mg/dl groups,
there were no differences in calcified plaque progression (9.3%/year vs
9.1%/year). We conclude that, with respect to LDL cholesterol lowering,
“lower is better” is not supported by changes in calcified plaque
progression.
——————————–
Primary Prevention- 20 mg Lipitor -one year F/U
Statins Reduced NON-Calcified Plaque Volume on CAT arteriography
19)
www.ncbi.nlm.nih.gov/pubmed/17287649
Invest Radiol. 2007 Mar;42(3):189-95.
Influence of a lipid-lowering therapy on calcified and noncalcified
coronary plaques monitored by multislice detector computed tomography:
results of the New Age II Pilot Study.
Burgstahler C, Reimann A, Beck T, Kuettner A, Baumann D, Heuschmid M,
Brodoefel H, Claussen CD, Kopp AF, Schroeder S. Source Department of
Internal Medicine, Division of Cardiology, Eberhard-Karls-University,
Tuebingen, Germany.
Abstract PURPOSE: Multislice detector computed tomography (MSCT) is
an accurate noninvasive modality to detect and classify different stages
of atherosclerosis. The aim of the New Age II Study was to detect
coronary lesions in men without established coronary artery disease
(CAD) but with a distinct cardiovascular risk profile. We also sought to
assess the effect after 1 year of a lipid-lowering therapy (LLT) using
20 mg of atorvastatin.
METHODS: Forty-six male patients (mean, 61 +/- 10 years) with an
elevated risk for CAD (PROCAM score >3 quintile) without LLT were
included.
Native and contrast-enhanced scans were performed in all patients. A
total of 27 of 46 patients received a follow-up scan (after 488 +/- 138
days). Coronary plaque burden (CP was assessed volumetrically.
RESULTS:
The prevalence of CAD was 83% (38/46 patients), and 11% (5/46) without coronary calcifications still had noncalcified plaques.
Total cholesterol and low-density lipoprotein cholesterol levels
decreased significantly under LLT ( Total cholesterol reduced from 225
to 162 , and LDL was reduced from 148mg/dL to 88 mg/dL.
On follow-up, calcium score and CPB remained unchanged (Agatston
score: 261 +/- 301 vs. 282 +/- 360; CPB: 0.149 +/- 0.108 vs. 0.128 +/-
0.075 mL, P > 0.05), whereas mean plaque volume of noncalcified
plaques decreased significantly from
0.042 +/- 0.029 mL versus
0.030 +/- 0.014 mL
(P < 0.05, mean reduction 0.012 +/- 0.017 mL or 24 +/- 13%).
CONCLUSIONS: Statin therapy led to a significant reduction (24%) of
noncalcified plaque burden that was not reflected in calcium scoring or
total plaque burden. This finding might explain the risk reduction after
the initiation of statin therapy.
Statins slowed progression of soft plaque, but not calcifications.
20)
http://www.ncbi.nlm.nih.gov/pubmed/20640900
Eur Radiol. 2010 Dec;20(12):2824-33. Epub 2010 Jul 18.
Influence of statin treatment on coronary atherosclerosis visualised using multidetector computed tomography.
Hoffmann H, Frieler K, Schlattmann P, Hamm B, Dewey M.
Department of Radiology, Charité, Medical School, Freie Universität
Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin,
Germany.
Coronary angiography using multidetector computed tomography (MDCT)
allows non-invasive assessment of non-calcified, calcified and mixed
plaques. Progression of coronary plaques may be influenced by statins.
Sixty-three consecutive patients underwent MDCT as a follow-up to
their original CT angiography in a retrospective longitudinal study.
MDCT was performed by using a voxel size of 0.5 × 0.35 × 0.35 mm(3) at
two time points 25 ± 3 months apart. Non-calcified, calcified and mixed
coronary plaque components were analysed by using volumetric
measurement. The influence of statin, low-density lipoprotein (LDL) and
risk factors was assessed by using a linear random intercept model for
plaque growth.
RESULTS:
The volumes of non-calcified, calcified and mixed coronary plaques
significantly (P < 0.001) increased from baseline
(medians/interquartile ranges = 21/15-39, 7/3-20 and 36/16-69 mm(3)) to
follow-up (29/17-44, 13/6-29 and 41/20-75 mm(3)).
Statins significantly slowed the growth of non-calcified plaques
(statin coefficient β = -0.0036, P = 0.01) but did not significantly
affect the growth rate of mixed or calcified plaques. The effect of
statin treatment on non-calcified plaques remained significant after
adjusting for LDL levels and cardiac risk factors.
CONCLUSION: Quantification using MDCT shows that progression of non-calcified coronary plaques may be slowed by statins.
CAC Coronary Calcium Scores and Statin Drugs
21)
circ.ahajournals.org/content/113/3/427.full
Coronary calcium Atorvastatin Effect of Intensive Versus Standard
Lipid-Lowering Treatment With Atorvastatin on the Progression of
Calcified Coronary Atherosclerosis Over 12 Months A Multicenter,
Randomized, Double-Blind Trial
Axel Schmermund, MD; Stephan Achenbach, MD; Thomas Budde, MD; Yuri
Buziashvili, MD; Andreas Förster, MD; Guy Friedrich, MD; Michael Henein,
MD; Gert Kerkhoff, MD; Friedrich Knollmann, MD; Valery Kukharchuk, MD;
Avijit Lahiri, MD; Roman Leischik, MD; Werner Moshage, MD; Michael
Schartl, MD; Winfried Siffert, MD; Elisabeth Steinhagen-Thiessen, MD;
Valentin Sinitsyn, MD; Anja Vogt, MD; Burkhard Wiedeking, MD; Raimund
Erbel, MD
——————————————————
Very Significant !!!!
Progression of CAC in patients on Statins Predicts increased risk for MI
22)
www.ncbi.nlm.nih.gov/pubmed/15059806 atvb.ahajournals.org/content/24/7/1272.long
Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1272-7. Epub 2004 Apr 1.
Progression of coronary artery calcium and risk of first myocardial
infarction in patients receiving cholesterol-lowering therapy.
Raggi P, Callister TQ, Shaw LJ. Source Tulane University School of Medicine, New Orleans, La, USA. praggi@tulane.edu
Abstract OBJECTIVE:
Statins reduce cardiovascular risk and slow progression of coronary
artery calcium (CAC). We investigated whether CAC progression and
low-density lipoprotein (LDL) reduction have a complementary prognostic
impact.
METHODS AND RESULTS: We measured the change in CAC in 495
asymptomatic subjects submitted to sequential electron-beam tomography
(EBT) scanning.
Statins were started after the initial EBT scan.
Myocardial infarction (MI) was recorded in 41 subjects during a
follow-up of 3.2+/-0.7 years. Mean LDL level did not differ between
groups (118+/-25 mg/dL versus 122+/-30 mg/dL, MI versus no MI).
On average, MI subjects demonstrated a CAC change of 42%+/-23% yearly;
Event-free subjects showed a 17%+/-25% yearly change (P=0.0001).
Relative risk of having an MI in the presence of CAC progression was
17.2-fold (95% CI: 4.1 to 71.2) higher than without CAC progression
(P<0.0001).
In a Cox proportional hazard model, the follow-up score (P=0.034) as
well as a score change >15% per year (P<0.001) were independent
predictors of time to MI.
CONCLUSIONS: Progression of CAC was significantly greater in patients
receiving statins who had an MI compared with event-free subjects
despite similar LDL control. Continued expansion of CAC may indicate
failure of some patients to benefit from statin therapy and an increased
risk of having cardiovascular events.
————————–
Regression of CAC with STATIN Therapy – Hong Kong
23)
www.ncbi.nlm.nih.gov/pubmed/20226020
Cardiovasc Ultrasound. 2010 Mar 12;8:5.
Outcome of coronary plaque burden: a 10-year follow-up of aggressive
medical management. Goh VK, Lau CP, Mohlenkamp S, Rumberger JA,
Achenbach S, Budoff MJ. Source Imaging Centre, Matilda International
Hospital, 41 Mount Kellett Road, The Peak, Hong Kong, SAR China.
Abstract BACKGROUND:
The effect of aggressive medical therapy on quantitative coronary
plaque burden is not generally known, especially in ethnic Chinese.
AIMS: We reasoned that Cardiac CT could conveniently quantify early
coronary atherosclerosis in our patient population, and hypothesized
that serial observation could differentiate the efficacy of aggressive
medical therapy regarding progression and regression of the
atherosclerotic process, as well as evaluating the additional impact of
life-style modification and the relative effects of the application of
statin therapy.
METHODS: We employed a standardized Cardiac CT protocol to serially
scan 113 westernized Hong Kong Chinese individuals (64 men and 49 women)
with Chest Pain and positive coronary risk factors. In all cases
included for this serial investigation, subsequent evaluation showed no
significantly-obstructive coronary disease by functional studies and
angiography.
After stringent risk factor modification, including aggressive statin
therapy to achieve LDL-cholesterol lowering conforming to N.C.E.P. ATP
III guidelines, serial CT scans were performed 1-12 years apart for
changes in coronary artery calcification (CAC), using the Agatston Score
(AS) for quantification.
RESULTS: At baseline, the mean AS was 1413.6 for males (mean age 54.4 years) and 2293.3 for females (mean age 62.4 years).
The average increase of AS in the entire study population was 24% per
year, contrasting with 16.4% per year on strict risk factor
modification plus statin therapy, as opposed to 33.2% per year for
historical control patients (p < 0.001).
Additionally, 20.4% of the 113 patients demonstrated decreasing
calcium scores. Medical therapy also yielded a remarkably low adverse
event rate during the follow-up period — 2 deaths, 2 strokes and only 1
case requiring PCI.
CONCLUSIONS: This study revealed that aggressive medical therapy can
positively influence coronary plaque aiding in serial regression of
calcium scores.
—–
Budoff Statins decreased rate of CAC progression in Diabetics – asymptomatic
24)
www.ncbi.nlm.nih.gov/pubmed/15990755
Am Heart J. 2005 Apr;149(4):695-700.
Diabetes and progression of coronary calcium under the influence of statin therapy.
Budoff MJ, Yu D, Nasir K, Mehrotra R, Chen L, Takasu J, Agrawal N, Liu
ST, Blumenthal RS. Source Division of Cardiology, Harbor-UCLA Medical
Center Research and Education Institute, Torrance, Calif 90502, USA.
Abstract BACKGROUND:
Coronary artery calcium (CAC) is a sensitive marker for the detection
of coronary heart disease (CHD). Coronary artery calcification can be
accurately quantified using electron beam tomography (EBT). We sought to
evaluate the progression of atherosclerosis in asymptomatic persons
with type 2 diabetes and measure the influence of statin therapy on CAC
progression.
METHODS: We evaluated 163 asymptomatic patients with type 2 diabetes
(120 men, 43 women). Patients were physician referred and underwent 2
consecutive EBT scans at least 1 year apart. Demographic data, risk
factors for CHD, and medication use were collected. Patients with
symptoms or known CHD were excluded.
RESULTS: The mean age was 65 +/- 10 years.
The mean CAC score at baseline was 651 +/- 414. Only 9 (6%) of 163 of
participants had scores of 0 at baseline. The time between scans
averaged 27 +/- 15 months.
Patients not treated with statins demonstrated a median annual increase in CAC progression of 20% (4%-44%),
whereas statin-treated patients demonstrated increase of 10% (4%-25%)
(P = .0001). Hemoglobin A 1c was weakly associated with CAC
progression.
CONCLUSIONS: Asymptomatic diabetic patients show a high prevalence of
atherosclerosis based on high frequency of coronary calcification.
Statin therapy induced a 50% reduction in the rate of CAC progression.
As rapid CAC progression has been associated with coronary events, EBT
may serve as a noninvasive method for following atherosclerosis and
response to therapy.
————
There is NO relationship Between Lipid scores and CAC !!!!!
25)
www.ncbi.nlm.nih.gov/pubmed/11179523
Am J Cardiol. 2001 Feb 15;87(4):406-12.
Relation of coronary artery calcium identified by electron beam
tomography to serum lipoprotein levels and implications for treatment.
Hecht HS, Superko HR, Smith LK, McColgan BP. Source Arizona Heart
Institute and Foundation, Phoenix 85006, USA.
Abstract This study was designed to determine whether the National
Cholesterol Education Program (NCEP) lipid guidelines accurately
identify subclinical atherosclerosis and whether low-density lipoprotein
cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)
levels are related to the extent and prematurity of coronary artery
disease (CAD) as determined by electron beam tomography (EBT).
Out of personal concern for CAD risk, 930 consecutive asymptomatic
subjects, without clinical CAD and on no lipid-lowering agents,
underwent EBT. Calcium score and percentile were correlated with total
cholesterol (TC), LDL-C, HDL-C, triglycerides, and demographic
parameters.
A calcium score of > 0 (EBT+) was found in 55% of patients;
45% of patients had a 0 score (EBT-).
Mean age (58.0 +/- 10.5 vs 49.3 +/- 9.7 years, p = 0.0001),
TC (218 +/- 39 vs 211 +/- 41 mg/dl, p = 0.006), LDL-C (136 +/- 36 vs 127 +/- 27 mg/dl, p = 0.005), and
TC/HDL-C (4.6 +/- 1.4 vs 4.2 +/- 1.5, p = 0.0001) were significantly
higher and HDL-C (52.2 +/- 17.6 vs 55.4 +/- 19.3 mg/dl, p = 0.008) lower
in the EBT+ compared with EBT- group.
In the EBT+ group, 75.1% of subjects had LDL-C < 160 mg/dl and
would not be advised to use lipid-lowering medications according to NCEP
guidelines. In subjects with LDL-C < 160 mg/dl, 51.8% of subjects
were EBT+, as were 46.1% of those with LDL-C < 100 mg/dl. There were
no significant differences in the calcium scores throughout the entire
range of all lipid parameters; calcium percentiles were virtually
identical within lipid value subgroups.
We conclude that asymptomatic patients with EBT-defined subclinical
atherosclerosis are not reliably identified by NCEP guidelines, and TC,
LDL-C, HDL-C, TC/HDL-C, and triglyceride levels do not correlate with
either the extent or prematurity of calcified plaque burden.
—————————————————————————–
Statin therapy induced a 61% reduction in the rate of coronary calcium progression !!!
26)
www.ncbi.nlm.nih.gov/pubmed/10867084
Am J Cardiol. 2000 Jul 1;86(1):8-11.
Rates of progression of coronary calcium by electron beam tomography.
Budoff MJ, Lane KL, Bakhsheshi H, Mao S, Grassmann BO, Friedman BC,
Brundage BH. Source Division of Cardiology, Saint John’s Cardiovascular
Research Center, Harbor-UCLA Medical Center Research and Education
Institute, Torrance, CA 90502, USA.
Abstract In this study, we sought to determine the rate of
progression of atherosclerosis using coronary calcium scores derived
from electron beam tomography (EBT). We studied a variety of disease
states (hypertension, high cholesterol, tobacco use, diabetes mellitus)
followed for 1 to 6.5 years.
We evaluated 299 asymptomatic persons (227 men and 72 women) who
underwent 2 consecutive EBT scans at least 12 months apart. The average
change in the calcium score (Agatston method) for the entire group was
33.2 +/- 9.2%/year.
The treated group (receiving statins) demonstrated an average
increase in calcium scores of 15 +/- 8%/year compared with 39 +/-
12%/year for untreated patients (p <0.001).
Among the 60 patients on statin monotherapy, 37% had a decrease in the calcium score from baseline to follow-up scan.
The relative increase in calcium scores did not vary significantly by
gender or risk factors, with the exception of statin-treated
hypercholesterolemic subjects.
Scores of zero on the initial scan portend a low likelihood of
significant calcific deposits on repeat scanning. Only 2 of 81
participants (2%) with scores of zero at baseline had scores >10 on
repeat study.
In this study, statin therapy induced a 61% reduction in the rate of
coronary calcium progression. This study demonstrates that EBT may be a
useful tool in assessing efficacy of different interventions to retard
progression of atherosclerosis, noninvasively, over relatively short
time periods.
—————————–
27)
http://circ.ahajournals.org/content/86/3/1026.full.pdf
Circulation Vol 86, No 3 September 1992
Health Policy on Blood Cholesterol Time to Change Directions Stephen B.
Hulley, MD, MPH; Judith M.B. Walsh, MD, MPH; and Thomas B. Newman, MD,
MPH
——————
28)
28) archinte.ama-assn.org/cgi/content/abstract/168/8/855
size=”2″>Arch Intern Med. 2008;168(8):855-860.
Thyrotropin Levels and Risk of Fatal Coronary Heart Disease, The HUNT Study
Recent studies suggest that relatively low thyroid function within
the clinical reference range is positively associated with risk factors
for coronary heart disease (CHD), but the association with CHD mortality
is not resolved.
Methods In a Norwegian population-based cohort study, we
prospectively studied the association between thyrotropin levels and
fatal CHD in 17 311 women and 8002 men without known thyroid or
cardiovascular disease or diabetes mellitus at baseline.
Results During median follow-up of 8.3 years, 228 women and 182 men
died of CHD. Of these, 192 women and 164 men had thyrotropin levels
within the clinical reference range of 0.50 to 3.5 mIU/L. Overall,
thyrotropin levels within the reference range were positively associated
with CHD mortality (P for trend = .01); the trend was statistically
significant in women (P for trend = .005) but not in men. Compared with
women in the lower part of the reference range (thyrotropin level,
0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95%
confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for
women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher
(thyrotropin level, 2.5-3.5 mIU/L) categories, respectively.
Conclusions Thyrotropin levels within the reference range were
positively and linearly associated with CHD mortality in women. The
results indicate that relatively low but clinically normal thyroid
function may increase the risk of fatal CHD.
Author Affiliations: Department of Public Health, Faculty of Medicine
(Drs Åsvold and Vatten), and Human Movement Science Programme (Dr
Nilsen), Norwegian University of Science and Technology, Trondheim,
Norway; St Olavs Hospital, Trondheim University Hospital, Trondheim (Dr
Åsvold); Department of Medical Biochemistry,
Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway (Dr Bjøro);
and Department of Social Medicine, University of Bristol, Bristol,
England (Dr Gunnell).
29)
http://www.eje-online.org/cgi/content/full/156/2/181
European Journal of Endocrinology, Vol 156, Issue 2, 181-186, 2007
CLINICAL STUDY The association between TSH within the reference range
and serum lipid concentrations in a population-based study. The HUNT
Study
Bjørn O Åsvold1,2, Lars J Vatten1, Tom I L Nilsen1 and Trine Bjøro3
1 Department of Public Health, Faculty of Medicine, Norwegian University
of Science and Technology, N-7489 Trondheim, Norway, 2 St Olavs
Hospital, Trondheim University Hospital, Trondheim, Norway and 3
Department of Medical Biochemistry, Rikshospitalet-Radiumhospitalet
Medical Center, Oslo, Norway
—————-
30)
www.endocrine-abstracts.org/ea/0025/ea0025p163.htm
Endocrine Abstracts (2011) 25 P163
Low testosterone predicts increased mortality and testosterone replacement therapy improves survival in men with type 2 diabetes
Vakkat Muraleedharan1,2, Hazel Marsh1 & Hugh Jones1,2 1
Barnsley Hospital NHS Foundation Trust, Barnley, UK; 2University of Sheffield, Sheffield, UK.
Background: Low testosterone in men is associated with increase in
all-cause and cardiovascular mortality. There is a high prevalence of
hypogonadism in men with type 2 diabetes and testosterone replacement
therapy (TRT) improves cardiovascular risk. However there is no
published data regarding mortality in these patients in relation to
testosterone levels, and the long term effect of TRT on mortality.
Aim: We report a 6 year follow-up study examining the effect of
baseline testosterone and TRT in hypogonadal men with type 2 diabetes on
all-cause mortality.
Methods: Five hundred eighty-seven patients with type 2 diabetes had
total testosterone (TT) performed between 2002 and 2005 and were
followed up for 5.8±1.3 years. Deaths during the first 6 months were
excluded.
Patients were then analysed in three groups.
i) normal TT (>10.4 nmol/l) (300 ng/dL)
ii) low TT (≤10.4 nmol/l) without TRT. (300 ng/dL)
iii) low TT receiving TRT for 2 years or more.
1nmol/L = 28.843 ng/dL
Results: Of 580 patients analysed, 338 had normal TT (58%) and 240
low TT (42%). In the low TT group 58 patients received TRT. Mean age
61±11 S.D. and similarly matched in all three groups. Total deaths 72
(12.4%).
Mortality rates –
low TT without treatment (36/182-20%),
normal TT (31/338-9%) and
low TT with TRT (5/58-8.6%).
Survival was significantly decreased in patients with low TT without
TRT (P=0.001 log rank) compared to normal. The treated group had
improved survival (P=0.049 log rank). In the Cox Regression model
multi-variate (age, weight, HbA1c, pre existing cardiovascular disease,
smoking, statin and ACEi/ARB use) adjusted hazard ratio for all-cause
mortality was 2.2 (95% CI 1.3–3.7 P=0.001) for low TT.
Conclusions: This study shows that men with type 2 diabetes and low
testosterone have a significant increased mortality. TRT improved
survival compared to those untreated, recording a similar mortality rate
to the normal TT group.
Brooke J. Poster 152. Muraleedharan V. Poster 163. Both presented at:
Society for Endocrinology BES 2011; April 11-14, 2011; Birmingham,
United Kingdom.
31)
http://www.endocrinology.org/press/pressreleases/2011-04-13_Testosterone.pdf
Society for Endocrinology – Media Release
Embargoed until 00:01 BST, Wednesday 13 April 2011
Increase in deaths in men with type 2 diabetes and testosterone deficiency may be prevented by testosterone replacement
————-
2011 WHI Follow Up Study shows less breast cancer in homone users.
32)
jama.ama-assn.org/content/305/13/1305.abstract
JAMA. 2011;305(13):1305-1314.
Health Outcomes After Stopping Conjugated Equine Estrogens Among
Postmenopausal Women With Prior Hysterectomy A Randomized Controlled
Trial Andrea Z. LaCroix, PhD; Rowan T. Chlebowski, MD, PhD;et al for the
WHI Investigators
Over the entire follow-up, lower breast cancer incidence in the CEE
group persisted and was 0.27% compared with 0.35% in the placebo group
(HR, 0.77; 95% CI, 0.62-0.95).
Original 2004 JAMA Report of Second Arm WHI
33)
http://jama.ama-assn.org/content/291/14/1701.full
JAMA. 2004;291(14):1701-1712.
Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy
The Women’s Health Initiative Randomized Controlled Trial ,The Women’s
Health Initiative Steering Committee by Garnet L. Anderson, PhD, WHI
Clinical Coordinating Center, Fred Hutchinson Cancer Research Center,
1100 Fairview Ave N, M3-A410, Box 19024, Seattle, WA 98109
5200 women CEE, 5200 placebo, with 7 year follow up
Cancer. Invasive breast cancer,
23% lower rate in the CEE group than in the placebo group (26 vs 33 per
10 000 person-years) . 94 CEE 124 placebo and this comparison
narrowly missed statistical significance (P = .06).
Results CEE vs placebo (average follow-up 6.8 years):
CHD, 0.91 (0.75-1.12) with 376 cases;
breast cancer, 0.77 (0.59-1.01) with 218 cases; (94 CEE and 124 placebo)
stroke, 1.39 (1.10-1.77) with 276 cases;
PE, 1.34 (0.87-2.06) with 85 cases;
colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and
hip fracture, 0.61 (0.41-0.91) with 102 cases.
————————————————————–
Editorial JAMA
34)
jama.ama-assn.org/content/305/13/1354.full
Editorial – JAMA. 2011;305(13):1354-1355.
Short-term Use of Unopposed Estrogen A Balance of Inferred Risks and
Benefits by Emily S. Jungheim, MD, MSCI; Graham A. Colditz, MD, DrPH
“the reduced incidence of breast cancer persisted. This finding is
inconsistent with a longstanding, corroborated body of evidence 7,8 and
raises the possibility that other important factors modify documented
risks and benefits of estrogen therapy among these long-term WHI
participants. ”
WHI Follow Study Lancet Oncology
35)
www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970075-X/abstract
The Lancet Oncology, Early Online Publication, 7 March 2012
Conjugated equine oestrogen and breast cancer incidence and mortality
in postmenopausal women with hysterectomy: extended follow-up of the
Women’s Health Initiative randomised placebo-controlled trial
Prof Garnet L Anderson PhD, Prof Rowan T Chlebowski MD b, Aaron K
Aragaki MS a, Prof Lewis H Kuller MD c, Prof JoAnn E Manson MD d, Prof
Margery Gass MD e, Elizabeth Bluhm MD f, Prof Stephanie Connelly MD g,
Prof F Allan Hubbell MD h, Prof Dorothy Lane MD i, Lisa Martin MD j,
Prof Judith Ockene PhD k, Prof Thomas Rohan MBBS l, Prof Robert Schenken
MD m, Prof Jean Wactawski-Wende PhD
Methods Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal
women from 40 US clinical centres into a randomised, double-masked,
placebo-controlled trial. Women aged 50—79 years who had undergone
hysterectomy and had expected 3-year survival and mammography clearance
were randomly allocated by a computerised, permuted block algorithm,
stratified by age group and centre, to receive oral conjugated equine
oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The
trial intervention was terminated early on Feb 29, 2004, because of an
adverse effect on stroke.
(It is well known that oral estrogen pills cause hypercoagulable state and increased stroke risk)
Follow-up continued until planned termination (March 31, 2005).
Consent was sought for extended surveillance from the 9786 living
participants in active follow-up, of whom 7645 agreed. Using data from
this extended follow-up (to Aug 14, 2009), we assessed long-term effects
of oestrogen use on invasive breast cancer incidence, tumour
characteristics, and mortality. We used Cox regression models to
estimate hazard ratios (HRs) in the intention-to-treat population.
Findings: After a median follow-up of 11·8 years (IQR 9·1—12·9), the
use of oestrogen for a median of 5·9 years (2·5—7·3) was associated with
lower incidence of invasive breast cancer (151 cases, 0·27% per year)
compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI
0·62—0·95; p=0·02) with no difference (p=0·76) between intervention
phase (0·79, 0·61—1·02) and post-intervention phase effects (0·75,
0·51—1·09).
In subgroup analyses, we noted breast cancer risk reduction with
oestrogen use was concentrated in women without benign breast disease
(p=0·01) or a family history of breast cancer (p=0·02).
In the oestrogen group, fewer women died from breast cancer (six
deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per
year; HR 0·37, 95% CI 0·13—0·91; p=0·03).
Fewer women in the oestrogen group died from any cause after a breast
cancer diagnosis (30 deaths, 0·046% per year) than did controls (50
deaths, 0·076%; HR 0·62, 95% CI 0·39—0·97; p=0·04).
Interpretation
Our findings provide reassurance for women with hysterectomy seeking
relief of climacteric symptoms in terms of the effects of oestrogen use
for about 5 years on breast cancer incidence and mortality.
Editorial in Lancet Oncology MArch 2012
36)
www.lancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970110-9/fulltext?_eventId=login
The Lancet Oncology, Early Online Publication, 7 March 2012
Oestrogen and breast cancer: results from the WHI trial by Anthony Howell and Jack Cuzick
“Young women (50—59 years) taking oestrogen were significantly less
likely to have coronary heart disease, myocardial infarction, and death
from all causes, not only with respect to older women but also placebo
controls of the same age. Observational and WHI studies agree on the
increased risk of breast cancer with combined hormone replacement
therapy (including a progestin). ”
“The WHI investigators should be congratulated for providing insight
into the value of conjugated equine oestrogens and young women can be
reassured of the low risks and potentially striking benefits,”
Men and Women
www.time.com/time/magazine/article/0,9171,1973295,00.html
Do Statins Work Equally for Men and Women?
By Catherine Elton Monday, Mar. 29, 2010 Read more:
www.time.com/time/magazine/article/0,9171,1973295,00.html#ixzz1oWwQ2L5v
Dangers of Statin Drugs – MAry Enig Weston Price
www.westonaprice.org/cardiovascular-disease/dangers-of-statin-drugs
Dangers of Statin Drugs: What You Haven’t Been Told About Popular
Cholesterol-Lowering Medicines written by Sally Fallon and Mary G. Enig,
PhD June 14 2004
Track Your Plaque- William Davis
www.trackyourplaque.com/blog/2012/03/why-are-heart-attacks-still-happening.html
Why are heart attacks still happening?
Posted on March 4, 2012 by Dr. William Davis
I’m a cardiologist. I see patients with heart disease in the form of
coronary artery disease every day. These are people who have undergone
bypass surgery, received one or more stents or undergone other forms of
angioplasty, have survived heart attacks or sudden cardiac death, or
have high heart scan scores. In short, I see patients every day who are
at high-risk for heart attack and death from heart disease. But I see
virtually no heart attacks. And nobody is dying from heart disease.
The tools to identify the potential for heart attack are available,
inexpensive, and simple. The strategies to reduce, even eliminate, risk
are likewise available, inexpensive, and cultivate overall health.
The followers of the Track Your Plaque program who
1) get a heart scan that yields a coronary calcium score (for long-term
tracking purposes) 2) identify the causes such as small LDL particles,
lipoprotein(a), vitamin D deficiency, and thyroid dysfunction
3) correct the causes
Dr Esselstyn
healthyyounetwork.org/archives/articles/pdf/Esselstyn_Caldwell_Article.pdf
Is the Present Therapy for Coronary Artery Disease the Radical
Mastectomy of the Twenty-First Century? Caldwell B. Esselstyn, Jr., MD*
fnadoc.techtrefoil.com/Health/weil_plus/engine2_diet/esselstyn2.pdf
Updating a 12-Year Experience With Arrest and Reversal Therapy for
Coronary Heart Disease (An Overdue Requiem for Palliative Cardiology) by
Caldwell B. Esselstyn, Jr., MD
=========================================================
—————————————————-
FDA Safety Warning
www.fda.gov/Drugs/DrugSafety/ucm293101.htm
FDA Drug Safety Communication:
Important safety label changes to cholesterol-lowering statin drugs
vailability Drug Safety and Availability Drug Alerts and Statements
Importing Prescription Drugs Medication Guides Drug Safety
Communications Drug Shortages Postmarket Drug Safety Information for
Patients and Providers Information by Drug Class Medication Errors FDA
Drug Safety Newsletter Drug Safety Podcasts Safe Use Initiative Drug
Recalls Drug Integrity and Supply Chain Security ? – Resources for You
FDA announces safety changes in labeling for some cholesterol-lowering
drugs
FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs
Facts about statins A class of prescription drugs used together with
diet and exercise to reduce blood levels of low-density lipoprotein
(LDL) cholesterol (“bad cholesterol”) Marketed as single-ingredient
products, including Lipitor (atorvastatin), Lescol (fluvastatin),
Mevacor (lovastatin), Altoprev (lovastatin extended-release), Livalo
(pitavastatin), Pravachol (pravastatin), Crestor (rosuvastatin), and
Zocor (simvastatin) Also marketed as combination products, including
Advicor (lovastatin/niacin extended-release), Simcor (simvastatin/niacin
extended-release), and Vytorin (simvastatin/ezetimibe)
Lovastatin Dose Limitations References Safety Announcement [2-28-2012]
The U.S. Food and Drug Administration (FDA) has approved important
safety label changes for the class of cholesterol- lowering drugs known
as statins. These changes were made to provide the public with more
information for the safe and effective use of statins and are based on
FDA’s comprehensive review of the statin class of drugs (see Data
Summary below).
The changes include the following: Monitoring Liver Enzymes Labels
have been revised to remove the need for routine periodic monitoring of
liver enzymes in patients taking statins.
The labels now recommend that liver enzyme tests should be performed
before starting statin therapy and as clinically indicated thereafter.
FDA has concluded that serious liver injury with statins is rare and
unpredictable in individual patients, and that routine periodic
monitoring of liver enzymes does not appear to be effective in detecting
or preventing serious liver injury. Adverse Event Information
Information about the potential for generally non-serious and reversible
cognitive side effects (memory loss, confusion, etc.) and reports of
increased blood sugar and glycosylated hemoglobin (HbA1c) levels has
been added to the statin labels. FDA continues to believe that the
cardiovascular benefits of statins outweigh these small increased risks.
Drug Interactions
The lovastatin label has been extensively updated with new
contraindications (situations when the drug should not be used) and dose
limitations when it is taken with certain medicines that can increase
the risk for muscle injury (see Lovastatin Dose Limitations below).
Healthcare professionals should refer to the drug labels for the latest
recommendations for prescribing statins (also see Additional Information
for Healthcare Professionals below). Patients should contact their
healthcare professional if they have any questions or concerns about
statins.
Additional Information for Patients
The statin drug labels have been revised to provide patients with
more information on the safe and effective use of statins. Patients
should be aware of the following information: There have been rare
reports of serious liver problems in patients taking statins. Patients
should notify their healthcare professional right away if they have the
following symptoms: unusual fatigue or weakness; loss of appetite; upper
belly pain; dark- colored urine; or yellowing of the skin or the whites
of the eyes. Memory loss and confusion have been reported with statin
use. These reported events were generally not serious and went away once
the drug was no longer being taken. Increases in blood sugar levels
have been reported with statin use. Certain medicines should never be
taken (are contraindicated) with lovastatin (Mevacor) (see Lovastatin
Dose Limitations below). Patients should contact their healthcare
professional if they have any questions or concerns about statins.
Patients should report side effects from the use of statins to the FDA
MedWatch program, using the information in the “Contact FDA” box at the
bottom of the page.
Additional Information for Healthcare Professionals
Healthcare professionals should perform liver enzyme tests before
initiating statin therapy in patients and as clinically indicated
thereafter. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment, therapy should
be interrupted. If an alternate etiology is not found, the statin should
not be restarted.
There have been rare post-marketing reports of cognitive impairment
(e.g., memory loss, forgetfulness, amnesia, memory impairment,
confusion) associated with statin use. These reported symptoms are
generally not serious and reversible upon statin discontinuation, with
variable times to symptom onset (1 day to years) and symptom resolution
(median of 3 weeks).
Increases in glycosylated hemoglobin (HbA1c) and fasting serum
glucose levels have been reported with statin use. Healthcare
professionals should follow the recommendations in the lovastatin label
regarding drugs that may increase the risk of myopathy/rhabdomyolysis
when used with lovastatin (see Lovastatin Dose Limitations below).
Healthcare professionals should report adverse events involving statins
to the FDA MedWatch program using the information in the “Contact FDA”
box at the bottom of this page.
Cognitive adverse events FDA reviewed the AERS database, the
published medical literature (case reports and observational
studies),4-13 and randomized clinical trials to evaluate the effect of
statins on cognition.14-17 The post-marketing adverse event reports
generally described individuals over the age of 50 years who experienced
notable, but ill- defined memory loss or impairment that was reversible
upon discontinuation of statin therapy. Time to onset of the event was
highly variable, ranging from one day to years after statin exposure.
The cases did not appear to be associated with fixed or progressive
dementia, such as Alzheimer’s disease. The review did not reveal an
association between the adverse event and the specific statin, the age
of the individual, the statin dose, or concomitant medication use.
Data from the observational studies and clinical trials did not
suggest that cognitive changes associated with statin use are common or
lead to clinically significant cognitive decline. Increases in
glycosylated hemoglobin (HbA1c) and fasting plasma glucose FDA’s review
of the results from the Justification for the Use of Statins in Primary
Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)
reported a 27% increase in investigator-reported diabetes mellitus in
rosuvastatin-treated patients compared to placebo-treated patients.
High-dose atorvastatin had also been associated with worsening glycemic
control in the Pravastatin or Atorvastatin Evaluation and Infection
Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22)
substudy.18 FDA also reviewed the published medical literature.19-26 A
meta-analysis by Sattar et al.,19 which included 13 statin trials with
91,140 participants, reported that statin therapy was associated with a
9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95%
confidence interval [CI] 1.02-1.17), with little heterogeneity (I2=11%)
between trials. A meta-analysis by Rajpathak et al.,20 which included 6
statin trials with 57,593 participants, also reported a small increase
in diabetes risk (relative risk [RR] 1.13; 95% CI 1.03-1.23), with no
evidence of heterogeneity across trials.
A recent study by Culver et al.,26 using data from the Women’s Health
Initiative, reported that statin use conveys an increased risk of
new-onset diabetes in postmenopausal women, and noted that the effect
appears to be a medication class effect, unrelated to potency or to
individual statin. Based on clinical trial meta-analyses and
epidemiological data from the published literature, information
concerning an effect of statins on incident diabetes and increases in
HbA1c and/or fasting plasma glucose was added to statin labels.
Lovastatin drug-drug interactions Information regarding drug-drug
interactions and contraindications and dose limitations has been added
to the lovastatin label.
————————
Kent Holtorf MD
www.sharecare.com/question/how-statins-heart-disease-stroke
How effective are statins in preventing heart disease and stroke? Dr.
Kent Holtorf answered: It is coming to light that the benefits of using
a statin for primary prevention have been greatly exaggerated and have
not been shown to be beneficial when compared to placebo. Evidence keeps
mounting that using a statin to lower cholesterol in someone without
known heart disease is of little if any benefit. In recent years,
fourteen major studies found no cardiovascular protection with statin
use in those without known heart disease or were halted because no
benefit was shown. A review study published in the Annals of Internal
Medicine analyzed the evidence of statin use for primary prevention.
Data was available for over 65,000 high risk patients who were treated
with statins to lower cholesterol for primary prevention. The study
found no benefit to treatment.
Joel Kauffman PHD
www.jpands.org/vol12no1/kauffman.pdf
Misleading Recent Papers on Statin Drugs in Peer-Reviewed Medical
Journals Joel M. Kauffman, Ph.D.
===================================================
PROSPER Study
www.thelancet.com/journals/lancet/article/PIIS0140-6736%2802%2911600-X/fulltext
The Lancet, Volume 360, Issue 9346, Pages 1623 – 1630, 23 November 2002
Pravastatin in elderly individuals at risk of vascular disease
(PROSPER): a randomised controlled trial Prof James Shepherd MD et al.
—————————————————————-
Shane Ellison
cochiro.com/2010/05/20/the-cholesterol-conspiracy/
The Cholesterol Conspiracy By drshane on May 20th, 2010
———————————-
www.thennt.com/statins-for-heart-disease-prevention-without-prior-heart-disease/
Statin Drugs Given for 5 Years for Heart Disease Prevention (Without Known Heart Disease)
In Summary, for those who took the statin for 5 years:
98% saw no benefit
0% were helped by being saved from death
1.6% were helped by preventing a heart attack
0.4% were helped by preventing a stroke
0.6% were harmed by developing diabetes*
In Other Words: None were helped (life saved)
1 in 60 were helped (preventing heart attack)
1 in 268 were helped (preventing stroke)
1 in 167 were harmed (develop diabetes*)
———————————————————
———————————————
AGED Garlic On Statins
www.ncbi.nlm.nih.gov/pubmed/15475033
Prev Med. 2004 Nov;39(5):985-91.
Inhibiting progression of coronary calcification using Aged Garlic
Extract in patients receiving statin therapy: a preliminary study.
Budoff MJ, Takasu J, Flores FR, Niihara Y, Lu B, Lau BH, Rosen RT,
Amagase H. Source Division of Cardiology, Harbor-UCLA Medical Center
Research and Education Institute, Torrance, CA 90502, USA.
Abstract BACKGROUND: Aged Garlic Extract (AGE) reduces multiple
cardiovascular risk factors, including blood pressure, cholesterol,
platelet aggregation and adhesion, while stimulating nitric oxide
generation in endothelial cells. However, no study has evaluated the
ability of AGE to inhibit vascular calcification, a marker of plaque
formation in human coronary arteries.
OBJECTIVE: To assess the efficacy of Aged Garlic Extract (AGE) on
changing the rate of atherosclerosis progression as compared to placebo.
DESIGN: A placebo-controlled, double-blind, randomized pilot study to
determine whether the atherosclerotic plaque burden detected by
electron beam tomography (EBT) will change at a different rate under the
influence of AGE as compared to placebo. Twenty-three patients were
enrolled, and 19 patients completed the study protocol. AGE 4 ml or the
equivalent amount of placebo was given to subjects. Duration of the
study was 1 year. S-allylcysteine (SAC), one of the active compound of
AGE, was measured in the blood as a compliance marker.
RESULTS: The mean change of the calcium score (volumetric method) for
the AGE group (n = 9) was 7.5 +/- 9.4% over 1 year. The placebo group
(n = 10) demonstrated an average increase in calcium scores of 22.2 +/-
18.5%, significantly greater than the treated cohort (P = 0.046).
There were no significant differences in individual cholesterol
parameters or C reactive protein between the groups. In patients
randomized to AGE, there was a nonsignificant trend for improving
cholesterol/high-density lipoprotein ratio (P = 0.07) and homocysteine
level (P = 0.08).
CONCLUSIONS: This small pilot study indicates the potential ability
of AGE to inhibit the rate of progression of coronary calcification, as
compared to placebo over 1 year. Should these findings be extended and
confirmed in larger studies, garlic may prove useful for patients who
are at high risk of future cardiovascular events.
——-
William DAvis Combined Approach- Vit D Omega 3
www.ncbi.nlm.nih.gov/pubmed/19092644
Am J Ther. 2009 Jul-Aug;16(4):326-32.
Effect of a combined therapeutic approach of intensive lipid
management, omega-3 fatty acid supplementation, and increased serum 25
(OH) vitamin D on coronary calcium scores in asymptomatic adults.
Davis W, Rockway S, Kwasny M. Source Milwaukee Heart Scan, Milwaukee, WI, USA.
Abstract The impact of intensive lipid management, omega-3 fatty
acid, and vitamin D3 supplementation on atherosclerotic plaque was
assessed through serial computed tomography coronary calcium scoring
(CCS).
Low-density lipoprotein cholesterol reduction with statin therapy has
not been shown to reduce or slow progression of serial CCS in several
recent studies, casting doubt on the usefulness of this approach for
tracking atherosclerotic progression.
In an open-label study, 45 male and female subjects with CCS of >
or = 50 without symptoms of heart disease were treated with statin
therapy, niacin, and omega-3 fatty acid supplementation to achieve l
ow-density lipoprotein cholesterol and triglycerides < or = 60 mg/dL;
high-density lipoprotein > or = 60 mg/dL; and
vitamin D3 supplementation to achieve serum levels of > or = 50 ng/mL 25(OH) vitamin D, in addition to diet advice.
Lipid profiles of subjects were significantly changed as follows:
total cholesterol -24%,
low-density lipoprotein -41%;
triglycerides -42%,
high-density lipoprotein +19%,
and mean serum 25(OH) vitamin D levels +83%.
After a mean of 18 months, 20 subjects experienced decrease in CCS with mean change of -14.5% (range 0% to -64%);
22 subjects experienced no change or slow annual rate of CCS increase of +12% (range 1%-29%).
Only 3 subjects experienced annual CCS progression exceeding 29% (44%-71%).
Despite wide variation in response, substantial reduction of CCS was
achieved in 44% of subjects and slowed plaque growth in 49% of the
subjects applying a broad treatment program.
————————-
2010
Statins have NO EFFECT ON CAC Progression in RANDOMIZED TRIALS !!!!
content.onlinejacc.org/cgi/content/full/56/20/1613
J Am Coll Cardiol, 2010; 56:1613-1622 STATE-OF-THE-ART PAPER
Coronary Artery Calcium Progression: An Important Clinical Measurement? A Review of Published Reports
John W. McEvoy, MB*,*, Michael J. Blaha, MD, MPH*, Andrew P.
DeFilippis, MD, MSc*, Matthew J. Budoff, MD{dagger}, Khurram Nasir, MD,
MPH*,{ddagger}, Roger S. Blumenthal, MD* and Steven R. Jones, MD*
We found that CAC progression correlates with worsening
atherosclerosis and may facilitate prediction of future cardiac events.
These findings support the notion that slowing CAC progression with
therapeutic interventions might provide prognostic benefit.
However, despite promising early data, such interventions (most
notably with statin therapy) have not been shown to slow the progression
of CAC in any randomized controlled trial to date, outside of post hoc
subgroup analyses.
——————————————-
LIPITOR WORSENED CAC Progression !!!! Randomized Trial
www.ncbi.nlm.nih.gov/pubmed/16449511
Heart. 2006 Sep;92(9):1207-12. Epub 2006 Jan 31.
Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial.
Houslay ES, Cowell SJ, Prescott RJ, Reid J, Burton J, Northridge DB,
Boon NA, Newby DE; Scottish Aortic Stenosis and Lipid Lowering Therapy,
Impact on Regression trial Investigators. Source Department of
Cardiology, Royal Infirmary, Edinburgh, UK.
Abstract OBJECTIVES:
To evaluate the effect of intensive lipid-lowering treatment on coronary
artery calcification in a substudy of a trial recruiting patients with
calcific aortic stenosis.
METHODS: In a double blind randomised controlled trial, 102 patients
with calcific aortic stenosis and coronary artery calcification were
randomly assigned by the minimisation technique to atorvastatin 80 mg
daily or matched placebo. Coronary artery calcification was assessed
annually by helical computed tomography.
RESULTS: 48 patients were randomly assigned to atorvastatin and 54 to
placebo with a median follow up of 24 months (interquartile range
24-30).
Baseline characteristics and coronary artery calcium scores were
similar in both groups. Atorvastatin reduced serum low density
lipoprotein cholesterol (-53%, p < 0.001) and C reactive protein
(-49%, p < 0.001) concentrations whereas there was no change with
placebo (-7% and 17%, p > 0.95 for both).
The rate of change in coronary artery calcification was 26%/year
(0.234 (SE 0.037) log arbitrary units (AU)/year; n = 39) in the
atorvastatin group and 18%/year (0.167 (SE 0.034) log AU/year; n = 49)
in the placebo group, with a geometric mean difference of 7%/year (95%
confidence interval -3% to 18%, p = 0.18).
Serum low density lipoprotein concentrations were not correlated with
the rate of progression of coronary calcification (r = 0.05, p = 0.62).
CONCLUSION: In contrast to previous observational studies, this
randomised controlled trial has shown that, despite reducing systemic
inflammation and halving serum low density lipoprotein cholesterol
concentrations, statin treatment does not have a major effect on the
rate of progression of coronary artery calcification.
—————————————————————————–
Statins HAve Same Effect on CAC as Placebo - Randomized Trial
www.ncbi.nlm.nih.gov/pubmed/17560880
Am J Cardiol. 2007 Jun 15;99(12):1714-7. Epub 2007 Apr 26.
Effect of simvastatin (80 mg) on coronary and abdominal aortic
arterial calcium (from the coronary artery calcification treatment with
zocor [CATZ] study).
Terry JG, Carr JJ, Kouba EO, Davis DH, Menon L, Bender K, Chandler
ET, Morgan T, Crouse JR 3rd. Source Department of Internal Medicine,
Wake Forest University Health Sciences, Winston-Salem, North Carolina,
USA.
Abstract We tested the hypothesis that, compared with placebo,
simvastatin would reduce the progression of coronary artery calcium
(CAC) and abdominal aortic calcium (AAC) levels in participants
asymptomatic for vascular disease.
Total CAC and AAC were measured with multidetector cardiac computed
tomography. Inclusion criteria were a CAC score of >or=50 Agatston
units, high-density lipoprotein (HDL) cholesterol levelor=2 other risk
factors. Diabetes and history of vascular disease were exclusion
criteria. Participants were randomized to receive 80 mg simvastatin
(n=40) or matching placebo (n=40) for 12 months. Lipids were measured at
3-month intervals, and CAC and AAC measurements were repeated at 6 and
12 months.
Total cholesterol, triglycerides, and LDL decreased significantly
with simvastatin treatment (p<0.0001 for all comparisons, adjusted
for baseline levels), whereas lipids remained unchanged for subjects
randomized to receive placebo.
Total CAC volume increased from baseline in both treatment groups.
For subjects in the active treatment group, CAC volume increased by
9%, whereas in the placebo group, plaque volume increased by 5% (p=0.12
for treatment effect). AAC volume also increased in both treatment
groups (p=0.15 for treatment effect).
In conclusion, simvastatin treatment does not reduce progression of CAC or AAC compared with placebo.
VVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVV
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
CAC USeless in Monitoring Therapy with Statins !!!! Review
archinte.ama-assn.org/cgi/content/full/169/22/2064 www.ncbi.nlm.nih.gov/pubmed/20008688
Arch Intern Med. 2009 Dec 14;169(22):2064-70.
Annual progression of coronary calcification in trials of preventive
therapies: a systematic review. McCullough PA, Chinnaiyan KM. Source
William Beaumont Hospital, Royal Oak, MI 48073, USA.
Abstract BACKGROUND:
Coronary artery calcification (CAC) measured by computed tomography
is radiographic confirmation of atherosclerosis, predicts cardiovascular
events, and has been evaluated as a surrogate measure in randomized
trials.
METHODS: We performed a literature search for prospective randomized
trials in which CAC was measured at baseline and at 1 year or more of
follow-up. We computed the weighted mean annualized rate of CAC
progression for a variety of therapies tested in these trials.
RESULTS: Ten trials (n = 2612) met our criteria and were included.
Electron-beam, double-helix, and multislice computed tomography were
used in 6, 2, and 2 trials, respectively. Agatston (8 trials) and
volumetric (2 trials) methods were used for CAC evaluation.
In 5 trials in subjects with cardiovascular disease (CVD) (n = 2135;
age, ~64 years; ~39% women; follow-up, ~26 months), therapies included
statins (n = 1370), placebo (n = 564), and antihypertensives (n = 201).
In 5 trials in subjects with chronic kidney disease (n = 477; age,
~55 years; ~34% women; follow-up, ~14 months), interventions included
low-phosphorus diet (n = 29), sevelamer hydrochloride (n = 229), and
calcium-based phosphate binders (n = 219).
The mean (SD) weighted annualized CAC increase overall and in
patients with CVD and chronic kidney disease was 17.2% (6.7%), 16.9%
(5.2%), and 18.4 (11.1%), respectively (P < .001). The rate among
those assigned blinded placebo was 14.6% (1.0%) (2 trials). There was no
consistent or reproducible treatment effect of any therapy on this
outcome measured at 1 year.
CONCLUSION: The 1-year change in CAC does not appear to be a suitable
surrogate end point for treatment trials in patients with CVD or
chronic kidney disease.
——————————————-
More severe disease warrants more sever therapies
www.ncbi.nlm.nih.gov/pubmed/19766749
Am J Cardiol. 2009 Oct 1;104(7):873-7.
Impact of coronary computed tomographic angiography findings on the
medical treatment and control of coronary artery disease and its risk
factors.
LaBounty TM, Devereux RB, Lin FY, Weinsaft JW, Min JK. Source
Department of Medicine, Division of Cardiology, Weill Cornell Medical
College, New York Presbyterian Hospital, New York, NY, USA.
Abstract
Although coronary computed tomographic angiography (CCTA) has high
diagnostic accuracy and increasing evidence of prognostic value for
coronary artery disease (CAD), its downstream clinical impact is not
established. In this study, the association of findings on CCTA with
subsequent treatment and control of CAD risk factors was assessed in 208
consecutive symptomatic outpatients without known CAD who underwent
CCTA. Blood pressure (BP), lipid levels, and CAD medications were
compared before and after CCTA (mean follow-up period 8.1 +/- 6.6
months). CAD severity on CCTA was graded as absent, mild (1% to 49%),
moderate (50% to 69%), or severe (> or =70%) stenosis.
In patients with absent, mild, moderate, and severe CAD on CCTA,
aspirin was initiated in 0%, 14%, 36%, and 15%;
statins were initiated or increased in 4%, 23%, 44%, and 42% of patients; and
BP medications were initiated or increased in 16%, 10%, 26%, and 38% of patients (p <0.05 for severe vs no CAD for all).
Higher grades of CAD severity were independently associated with
greater post -CCTA use of aspirin (odds ratio 3.2 per grade, p
<0.001) and statins (odds ratio 3.6 per grade, p <0.001), but not
BP medications. Greater CAD severity was independently associated with
lower post-test total cholesterol (-8.2 mg/dl per grade, p = 0.02),
low-density lipoprotein cholesterol (-6.8 mg/dl per grade, p = 0.04),
and diastolic BP (-1.4 mm Hg per grade, p = 0.03), but not systolic BP.
In conclusion, greater CAD severity on CCTA is associated with
enhanced medical treatment and improved control of CAD risk factors.
—————————————————————-
Do a CAC and then a sestamibi Nuclear perusion scan for high risk patients
www.ncbi.nlm.nih.gov/pubmed/20630895 www.rodiag.ch/documents/download/ehj2010_wg%20statmenet%20ct%20spect%20risk%20strat.pdf
Eur Heart J. 2011 Aug;32(16):1986-93, 1993a, 1993b. Epub 2010 Jul 14.
Cardiac computed tomography and myocardial perfusion scintigraphy for
risk stratification in asymptomatic individuals without known
cardiovascular disease: a position statement of the Working Group on
Nuclear Cardiology and Cardiac CT of the European Society of Cardiology.
Perrone-Filardi P, Achenbach S, Möhlenkamp S, Reiner Z, Sambuceti G,
Schuijf JD, Van der Wall E, Kaufmann PA, Knuuti J, Schroeder S,
Zellweger MJ. Source Department of Internal Medicine, Cardiovascular
Sciences and Immunology, Federico II University of Naples, Via Pansini,
5, 80131, Napoli, Italy.
18% of CAC 100-400 and 45% CAC >400 had subclinical myocardial ischemia
www.ncbi.nlm.nih.gov/pubmed/15295414
J Nucl Cardiol. 2004 Jul-Aug;11(4):450-7. Prevalence of silent
myocardial ischemia in asymptomatic individuals with subclinical
atherosclerosis detected by electron beam tomography. Anand DV, Lim E,
Raval U, Lipkin D, Lahiri A.
Source Cardiac Imaging and Research Centre, The Wellington Hospital, London, United Kingdom.
Abstract BACKGROUND:
Electron beam tomography coronary calcium imaging is an evolving
technique for the early detection of coronary atherosclerosis, and
recent studies have established its prognostic value in asymptomatic
individuals. The relationship of coronary artery calcium scores (CAC) to
obstructive coronary artery disease (CAD) has been poorly studied but
is clinically relevant because it determines which individuals are
likely to benefit from revascularization procedures. Hence, we
prospectively evaluated the prevalence of myocardial ischemia in
asymptomatic patients with cardiovascular risk factors and subclinical
atherosclerosis.
METHODS AND RESULTS:
We studied 864 asymptomatic patients with no previous CAD but with
cardiovascular risk factors, referred for electron beam tomography
coronary calcium imaging to our institution over an 18-month period.
From this group, 220 consecutive patients (85% men; mean age, 61 +/- 9
years; age range, 31-84 years) with moderate to severe atherosclerotic
disease (coronary calcium score > or =100 Agatston units) were
prospectively evaluated by technetium 99m sestamibi single photon
emission computed tomography (SPECT). Patients were followed up (mean
follow-up, 14 months) and data regarding their subsequent clinical
management recorded.
Of the 220 patients, 119 had moderate atherosclerosis (CAC score of
100-400 Agatston units) and 101 had severe atherosclerosis (CAC score
> or =400 Agatston units).
Abnormal SPECT findings were seen in 18% of patients with moderate
atherosclerosis (n = 21) and 45% of patients with severe atherosclerosis
(n = 45).
Increasing severity of atherosclerosis was related to increasing
ischemic burden (summed difference score = 1 +/- 0.2 for CAC score of
100-400 Agatston units and 3.2 +/- 0.5 for CAC score > or =400
Agatston units). In a multivariate linear regression model incorporating
risk factors, CAC was the only predictor of silent ischemia.
CONCLUSION: In comparison to previously published data, we detected a
higher prevalence of silent ischemia even in patients with moderate
coronary atherosclerosis (18%). This may reflect the differing risk
factor profile of our patient population. When coronary calcium
screening is used to preselect asymptomatic patients with cardiovascular
risk factors for myocardial perfusion imaging, the optimum coronary
calcium score threshold will depend on the population prevalence of risk
factors and asymptomatic obstructive CAD.
—————————
BIO-Identical Hormones and Preventing CAD
with ESTROGEN
HRT(Premarin Alone) treatment inhibited the progression of atherosclerosis by 63% !!!! CAC Scoring in WHI Study by Budoff
Estrogen Treatment in Post Menopause reduced progession of Calcium score – BUDOFF
www.ncbi.nlm.nih.gov/pubmed/15989413
J Womens Health (Larchmt). 2005 Jun;14(5):410-7.
Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography.
Budoff MJ, Chen GP, Hunter CJ, Takasu J, Agrawal N, Sorochinsky B, Mao S.
Source Division of Cardiology, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA.
Abstract PURPOSE: The recent Women’s Health Initiative (WHI) results
have demonstrated that combined estrogen plus progestin imparts a small
but significant increase in cardiovascular risk and breast cancer among
asymptomatic women.
However, the effect and potential benefit of unopposed estrogen is
not as clear. We sought to evaluate the progression of subclinical
atherosclerosis in postmenopausal women using no hormone replacement
therapy (HRT), combined therapy, and estrogen alone in an observational
study.
METHODS: Postmenopausal women without symptoms or known coronary
heart disease (CHD) were evaluated at our center for follow-up of
coronary calcification. Patients were physician referred and underwent
two consecutive electron beam tomography scans at least 1 year apart.
All women fitting the study criteria were asked to participate, and
those who consented were included. Demographic data, risk factors for
CHD, HRT, and other medication use were collected by interview.
RESULTS: The study included 177 asymptomatic women.
Calcium progression was 14.6%+/-21% in women taking any hormone
therapy (n=97). Annual calcium progression rates in nonusers (n=80) was
22.3%+/-32%.
Relative to the nonuser group, HRT treatment inhibited the
progression of atherosclerosis by 35% (p=0.01). This effect was
independent of age, risk, cardiovascular factors, statin use, or
baseline CAC score.
Thirty-five of the 97 women (36%) were taking estrogen plus
progestin, with an annual increase in calcium scores of 24%+/-23%,
similar to the non-HRT women (22%).
Those women taking estrogen replacement only (n=62) was 63% lower (9%+/-22%).
CONCLUSIONS: This is an observational study, and the results are in
accordance with the recently published WHI study, demonstrating no
benefit of estrogen plus progestin compared with no therapy. However,
women taking unopposed estrogen demonstrated a significant slowing of
subclinical atherosclerosis compared with non-HRT and estrogen plus
progestin.
———-
Estrogen Therapy and Coronary-Artery Calcification
N Engl J Med 2007; 356:2591-2602June 21, 2007 by JoAnn E. Manson, M.D.,
Dr.P.H., Matthew A. Allison, M.D., et al. for the WHI and WHI-CACS
Investigators
Results:
The mean coronary-artery calcium score after trial completion was
lower among women receiving estrogen (83.1) than among those receiving
placebo (123.1) (P=0.02 by rank test). The new findings from WHI-CACS
indicate that estrogen therapy initiated in women at 50 to 59 years of
age is related to a reduced plaque burden in the coronary arteries and a
reduced prevalence of subclinical coronary artery disease, providing
support for the hypothesis that estrogen therapy may have
cardioprotective effects in younger women.
——————————————————————–
www.ncbi.nlm.nih.gov/pmc/articles/PMC2751659/
Menopause. 2008 Jul–Aug; 15(4 Pt 1): 639–647.
Oophorectomy, hormone therapy, and subclinical coronary artery disease
in women with hysterectomy: the Women’s Health Initiative coronary
artery calcium study
Matthew A. Allison, MD, MPH,1 JoAnn E. Manson, MD, et al. for the
Women’s Health Initiative and Women’s Health Initiative Coronary Artery
Calcium
Abstract Objective
Surgical menopause has been associated with an increased risk of
coronary heart disease events. In this study, we aimed to determine the
associations between coronary artery calcium (CAC) and hysterectomy,
oophorectomy, and hormone therapy use with a focus on the duration of
menopause for which there was no hormone therapy use.
Design In a substudy of the Women’s Health Initiative
placebo-controlled trial of conjugated equine estrogens (0.625 mg/d), we
measured CAC by computed tomography 1.3 years after the trial was
stopped.
Participants included 1,064 women with previous hysterectomy, aged 50
to 59 years at baseline. The mean trial period was 7.4 years.
Imaging was performed at a mean of 1.3 years after the trial was stopped.
Results Mean age was 55.1 years at randomization and 64.8 years at CAC measurement.
In the overall cohort, there were no significant associations between
bilateral oophorectomy, years since hysterectomy, years since
hysterectomy without taking hormone therapy (HT), years since bilateral
oophorectomy, and years of HT use before Women’s Health Initiative
enrollment and the presence of CAC.
However, there was a significant interaction between bilateral
oophorectomy and prerandomization HT use for the presence of any CAC (P =
0.05). When multivariable analyses were restricted to women who
reported no previous HT use, those with bilateral oophorectomy had an
odds ratio of 2.0 (95% CI: 1.2–3.4) for any CAC compared with women with
no history of oophorectomy, whereas among women with unilateral or
partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0–2.8).
Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower prevalence of CAC.
Conclusions : Among women with previous hysterectomy, subclinical
coronary artery disease was more prevalent among those with oophorectomy
and no prerandomization HT use, independent of traditional
cardiovascular disease risk factors. The results suggest that factors
related to oophorectomy and the absence of estrogen treatment in
oophorectomized women may be related to coronary heart disease.
—
www.ncbi.nlm.nih.gov/pubmed/19811237
Climacteric. 2009;12 Suppl 1:26-31.
Premature menopause increases cardiovascular risk. by Archer DF.
Source Eastern Virginia Medical School, Norfolk, Virginia, USA.
Abstract Premature menopause and bilateral oophorectomy in young
women are associated with an increased incidence of cardiovascular
disease, myocardial infarction and overall mortality. Observational
studies suggest an interval of 5-10 years between loss of ovarian
function and the increased risk of cardiovascular disease. This finding
is consonant with a published autopsy study of women who had undergone
bilateral oophorectomy. The progression of atherosclerosis is retarded
with the use of estrogen replacement therapy in non-human primates and
women. Hormone therapy reduced the incidence of cardiovascular disease
in women following bilateral oophorectomy. These findings support the
use of hormone therapy in young women who have lost ovarian function.
—-
humupd.oxfordjournals.org/content/16/2/131.full
Hum. Reprod. Update (2010) 16 (2): 131-141.
Should the ovaries be removed or retained at the time of hysterectomy
for benign disease? M. Hickey1, M. Ambekar, and I. Hammond School of
Women’s and Infants’ Health, University of Western Australia, King
Edward Memorial
————————–
VERY IMPORTANT !!!!!
www.srm-ejournal.com/article.asp?AID=8985
Sexuality, Reproduction & Menopause Vol. 18, No. 4 / October 2010 Vol. 18, No. 4 / October 2010
Menopausal Medicine: For clinicians who provide care for women
Prophylactic bilateral oophorectomy jeopardizes long-term health by
Lynne T. Shuster, MD Director, Women’s Health Clinic, Assistant
Professor of Medicine, Department of Internal Medicine, College of
Medicine, Mayo Clinic, Rochester, Minnesota
Approximately 4.5 million women in the United States have undergone
bilateral oophorectomy before reaching natural menopause, yet
accumulating evidence indicates that surgical removal of the ovaries
increases the risk of long-term deleterious outcomes.1-4 Bilateral
oophorectomy refers to the simultaneous or sequential removal of both
ovaries. The surgery may be performed for a malignancy, benign disease
of the ovaries (eg, endometriosis or a cyst), or prophylaxis against
cancer. Oophorectomy is most commonly performed along with hysterectomy.
Although age-adjusted rates of prophylactic oophorectomy have decreased
over time, the proportion of hysterectomies accompanied by prophylactic
oophorectomy in the United States has actually increased, from 29% in
1979 to 45% in 2004.5
Women who experience the premature loss of ovarian function as a
result of bilateral oophorectomy performed before the onset of natural
menopause are at increased risk for death, cardiovascular disease,
stroke, lung cancer, cognitive impairment or dementia, parkinsonism,
osteoporosis, depressive or anxiety symptoms, and sexual dysfunction.2-4
The risks appear to be greater for women who are younger at the time of oophorectomy.2,6,7
Some studies, however, show that even women who underwent ooph-
orectomy after the onset of natural menopause had an increased risk of
deleterious outcomes.3
Health care practitioners who advise women about bilateral
oophorectomy need to be aware of the risk-benefit balance and counsel
patients accordingly. For premenopausal women who are not at markedly
increased risk for ovarian or breast cancer, prophylactic oophorectomy
should be discouraged
The risk-benefit balance for prophylactic bilateral oophorectomy in younger women at average risk of ovarian or breast cancer
Modified from Shuster LT et al. Menopause Int. 2008;14:111-116.
Long-term consequences of prophylactic bilateral oophorectomy
Numerous studies demonstrate that surgical ovarian loss has a long-term
harmful impact on women’s health, especially for women who undergo
oophorectomy before natural meno-pause. The following discussion
provides an overview of specific health effects.
All-cause mortality :Bilateral oophorectomy is associated with excess
all-cause mortality. The mayo clinic cohort Study of Oophorectomy and
Aging showed increased overall mortality in women who underwent
prophylactic bilateral oophorectomy before age 45 years compared with
referent women (hazard ratio [HR], 1.67; 95% confidence interval [CI],
1.16-2.40).8 The increased mortality was mainly observed in those women
who did not take estrogen up to the age of 45 years (HR, 1.93; 95% CI,
1.25-2.96). In a study using a Markov decision analysis model, Parker
and colleagues projected that women undergoing oophorectomy before age
55 years would have an 8.6% excess mortality by age 80 years, and women
up to age 59 years undergoing oophorectomy would have an excess
mortality of 3.9%.9 The authors concluded that, in the absence of a
specific medical indication for bilateral oophorectomy, ovarian
conservation until at least age 65 years benefits survival.
Parker and colleagues subsequently reported on mortality and
long-term health outcomes after oophorectomy or ovarian conservation in
the Nurses’ Health Study. A total of 29,380 women underwent
hysterectomy, of whom 45% had bilateral oophorectomy and 44% had ovarian
conservation at the time of hysterectomy.3
Oophorectomy increased the risk of death from all causes (HR, 1.12;
95% CI, 1.03-1.21), and there was not a significant difference in risk
by age at the time of oophorectomy. The authors calculated that for
every 24 women who undergo bilateral oophorectomy, at least 1 woman will
die prematurely as a result of the oophorectomy.3
Cardiovascular disease : In a 2006 meta-analysis evaluating 11
studies of menopausal status and age at menopause, the pooled relative
risk of cardiovascular disease in women who underwent bilateral
oophorectomy was 2.62 (95% CI, 2.05-3.35) compared with women who were
premenopausal.10
This compared with a relative risk of 1.14 (95% CI, 0.86-1.51) for natural menopause versus premenopausal status.
The pooled effect of bilateral oophorectomy before age 50 years compared with after age 50 years was 4.55 (95% CI, 2.56-8.01).10
The danish Nurse cohort Study showed an adjusted HR of 8.7 (95% CI,
2.0-38.1) for ischemic heart disease among women who underwent bilateral
oophorectomy before age 40 years compared with after age 45 years.7
The risk was much smaller among women who experienced natural menopause before age 40 years (HR, 2.2; 95% CI, 1.0-4.9).
Estrogen use by women who underwent bilateral oophorectomy was
associated with a significant reduction in risk of ischemic heart
disease (HR, 5.5 among ever-users versus 16.2 among never-users), and
the relative benefit was most pronounced for women who were current
users or started treatment within 1 year after oophorectomy.
In the Nurses’ Health Study, there was a slightly increased risk of
coronary heart disease in the women who had bilateral oophorectomy
versus ovarian conservation (HR, 1.17; 95% CI, 1.02-1.35) and a further
increase in risk for women undergoing oophorectomy before age 45 years
(HR, 1.26; 95% ci, 1.04-1.54).
Women who underwent bilateral oophorectomy before age 50 years and
did not receive estrogen treatment also had an increased risk of stroke
(HR, 2.19; 95% CI, 1.16-4.14).3
The preponderance of evidence suggests that bilateral oophorectomy is
associated with increased cardiovascular risk and premature cardiac
death, and oophorectomy at a young age further increases this risk.
Estrogen therapy started early after a bilateral oophorectomy or after a
premature or early natural menopause appears to reduce this risk.7,11
Lung cancer : In the Nurses’ Health Study, both lung cancer incidence
and mortality were increased in women who underwent hysterectomy with
oophorectomy compared with those who had ovarian conservation (HR for
incidence, 1.26; 95% CI, 1.02-1.56; HR for mortality, 1.31; 95% CI,
1.02-1.68).3 Unfortunately, there are no other studies of this
association.
Cognitive impairment or dementia
In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who
underwent bilateral oophorectomy before the onset of menopause had an
increased risk of cognitive impairment or dementia compared with
referent women (HR, 1.33; 95% CI, 0.98-1.81; P=.07).
The risk increased with younger age at oophorectomy, and women who
underwent oophorectomy before age 43 years had the greatest risk (HR,
1.74; 95% CI, 0.97-3.14; P=.06). However, the increased risk with
younger age at oophorectomy was restricted to women who underwent
oophorectomy before age 49 years and did not take estrogen until they
were at least 50 years of age (HR, 1.89; 95% CI, 1.27-2.83;
P=.002).12,13 Several observational studies identified a 20% to 40%
reduction in the risk of dementia for women who started estrogen therapy
around the time of menopause.14,15
By contrast, the Women’s Health initiative memory Study controlled
clinical trials did not confirm a cognitive benefit of estrogen, but
rather showed an increased risk of cognitive impairment or dementia in
women who initiated estrogen at age 65 years or older.16
Unfortunately, current information about the effect of estrogen
treatment on risk of cognitive decline or dementia remains inadequate
for women who have undergone bilateral oophorectomy or have experienced
premature or early natural menopause.17
Small prospective trials evaluating neurocognitive function after
bilateral oophorectomy have identified a significant decrease in
specific cognitive functions, including verbal fluency, verbal memory,
procedural learning, and some other executive functions.2,15
Neurocognitive performance was worse when oophorectomy occurred at a
younger age and worse with greater declines in estradiol levels, but it
was better when hormone therapy was initiated after oophorectomy.15
It is important to note that some of these studies did not evaluate
the effects of estrogen on vasomotor symptoms and sleep disruption,
which can also affect neurocognitive performance.
Women who undergo bilateral oophorectomy at younger ages appear to be
at an increased risk for cognitive impairment or dementia; estrogen
therapy may be particularly important for neuroprotection in these
women.15,18
Further studies are needed to confirm this association.
Parkinsonism and Parkinson’s disease
In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who
underwent bilateral oophorectomy before the onset of menopause had an
increased risk of parkinsonism (a neurological syndrome that includes
Parkinson’s disease) compared with referent women (HR, 1.78; 95% CI,
1.06-3.01; P=.03), and the risk increased with younger age at
oophorectomy (test for linear trend; P=.02). The findings were also
consistent specifically for Parkinson’s disease, but did not reach
statistical significance.13,19
Osteoporosis Oophorectomy
before age 45 years is a well-established risk factor for
osteoporosis.20 Even in women who undergo bilateral oophorectomy after
natural menopause, the risk for osteoporotic fractures may be increased
compared with the risk in women who have intact ovaries.21 Although
estrogen may reduce this risk, nonhormonal alternative treatments are
now generally used to prevent osteoporosis.
Mental health and sexual function Although some studies report that
hysterectomy performed for benign disease is associated with improved
psychological well-being and quality of life, early bilateral
oophorectomy along with hysterectomy is more commonly associated with
worsened psychological well- being and negative affect.1
In a prospective study of 101 women, those who underwent oophorectomy
along with hysterectomy had significantly greater anxiety and
depression and less positive well-being than women who underwent
hysterectomy alone.22
However, women who took estrogen after the oophorectomy reported less
anxiety and depression, and their psychological well-being was similar
to that of the women whose ovaries were conserved. Similarly,
oophorectomized women reported more impaired sexual function compared
with women who had intact ovaries, but their sexual symptoms were not
ameliorated by taking estrogen.22
The mayo clinic cohort Study of Oophorectomy and Aging followed 666
women with bilateral oophorectomy and 673 referent women, using
structured questionnaires and telephone interviews to assess depressive
and anxiety symptoms. Women who underwent bilateral oophorectomy before
the onset of natural menopause had an increased risk of developing
depressive (HR, 1.54; 95% CI, 1.04-2.26) and anxiety symptoms (HR, 2.29;
95% CI, 1.33-3.95).23
The increase in depressive and anxiety symptoms occurred in women who
had not suffered from depression or anxiety before the surgery, and
persisted many years after surgery. Several studies have reported
negative psychosocial and sexual outcomes among women undergoing
prophylactic oophorectomy because of an increased risk for ovarian
cancer. madalinska and colleagues identified more frequent problems of
dyspareunia and decreased sexual satisfaction in women who underwent
prophylactic oophorectomy compared with women who underwent only medical
surveillance.24
Other smaller cohort studies similarly showed an increased risk of
dyspareunia and a decrease in sexual satisfaction following prophylactic
bilateral oophorectomy in women at increased risk for cancer.2
Adverse effects of bilateral oophorectomy on sexual function may
involve several different domains, including libido, arousal, and
orgasm.1 In a survey of european women not known to be at increased risk
of cancer, those who underwent bilateral oophorectomy were twice as
likely to have symptoms of hypoactive sexual desire disorder compared
with women who were premenopausal or experienced natural menopause.25
———————————–
DANISH Nurse Cohort Study-
Both Menopause AND Ovarectomy Associated with Increased CAD
www.ncbi.nlm.nih.gov/pubmed/15955642
Maturitas. 2006 Jan 20;53(2):226-33. Epub 2005 Jun 13.
The association between early menopause and risk of ischaemic heart disease: influence of Hormone Therapy.
Løkkegaard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B,
Pedersen AT. Source The Danish Nurse Cohort Study, Center for Alcohol
Research, National Institute of Public Health, Denmark.
Abstract Randomised clinical trials find no protection against
development of ischaemic heart disease by use of Hormone Therapy (HT)
after the age of 50 years. Observational studies suggest that early
menopause is a risk factor for ischaemic heart disease. Yet, a clinical
very relevant question is whether HT reduces this risk associated with
early menopause.
OBJECTIVE: To analyse whether early menopause based on various causes
are independent risk factors for ischaemic heart disease, and to
investigate whether the risks are modified by use of HT.
METHODS: In a prospective cohort study questionnaires were mailed to
Danish female nurses above 44 years of age in 1993. Information on
menopause, use of HT and lifestyle was obtained. In total 19,898 (86%)
nurses fulfilled the questionnaire, among them 10.533 were
postmenopausal with definable menopausal age, free of previous ischaemic
heart disease, stroke or cancer. Through individual linkage to national
register incident cases of ischaemic heart disease were identified
until end of 1998.
RESULTS: Menopause below both age 40 and 45 was associated with an
increased risk of ischaemic heart disease, seeming most pronounced for
women who had an early ovariectomy but also among spontaneous menopausal
women.
Generally HT did not reduce the risk except for the early-
ovariectomised women, where no increased risk of ischaemic heart disease
for HT users was found.
CONCLUSION: We found an increased risk of ischaemic heart disease
associated with early removal of the ovaries that might be reduced with
HT. The present study need confirmation from other studies but suggests
that early ovariectomised women could benefit from HT.
————————————–
n.b5z.net/i/u/10124624/f/Oestrogen_and_Skin_Ageing.pdf
Biogerontology March 2011
The role of estrogen deficiency in skin ageing and wound healing Elaine Emmerson • Matthew J. Hardman
Received: 26 November 2010 / Accepted: 11 February 2011
Springer Science+Business Media B.V. 2011
Conclusions and further perspectives
Despite links between estrogen and ageing being suggested many years
ago, only over the last decade has estrogen emerged as a key determinant
of ageing in peripheral non-reproductive tissues, particularly bone,
skin and brain. Indeed, the endocrine theory of ageing, underpinned by
germline cell ablation experiments in model organisms, states that
chronological changes in hormones levels accelerate the cellular effects
of ageing. In skin particularly, it is only over the last few years
that we have begun to understand the relative contributions of hormones
and ageing to pathological healing. Indeed, although our knowledge of
estrogen’s beneficial effects on wound repair has greatly expanded over
recent years there is still much that is not
——————————————-
———————————–
www.freewebs.com/stopped_our_statins/Cholesterol%20Lowering%20Drugs%20-%20Shane%20Ellison.pdf
This is Very Good !!!!!!!
www.scribd.com/doc/74463065/6/Statin-Drugs-%E2%80%93-Are-they-Safe-and-Effective www.scribd.com/doc/74463065/6/Statin-Drugs-%E2%80%93-Are-they-Safe-and-Effective
shane ellison
The Hidden Truth About Cholsterol Drugs Hidden TruthAboutCholesterol-Lowering Drugs!, the book
——————————————————————–
Bioidentical Esdtrogen prevents CAD
www.ncbi.nlm.nih.gov/pubmed/11119394
Ann Intern Med. 2000 Dec 19;133(12):933-41.
A prospective, observational study of postmenopausal hormone therapy
and primary prevention of cardiovascular disease. Grodstein F, Manson
JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. Source Channing
Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.
Abstract BACKGROUND: Most primary prevention studies have found that
long-term users of postmenopausal hormone therapy are at lower risk for
coronary events, but numerous questions remain. An adverse influence of
hormone therapy on cardiovascular risk has been suggested during the
initial year of use; however, few data are available on short-term
hormone therapy. In addition, the cardiovascular effects of daily doses
of oral conjugated estrogen lower than 0.625 mg are unknown, and few
studies have examined estrogen plus progestin in this regard.
OBJECTIVE: To investigate duration, dose, and type of postmenopausal
hormone therapy and primary prevention of cardiovascular disease.
DESIGN: Prospective, observational cohort study.
SETTING: Nurses’ Health Study, with follow-up from 1976 to 1996.
PATIENTS: 70 533 postmenopausal women, in whom 1258 major coronary
events (nonfatal myocardial infarction or fatal coronary disease) and
767 strokes were identified.
MEASUREMENTS: Details of postmenopausal hormone use were ascertained
by using biennial questionnaires. Cardiovascular disease was established
by using a questionnaire and was confirmed by medical record review.
Logistic regression models were used to calculate relative risks and 95%
CIs, adjusted for confounders.
RESULTS: When all cardiovascular risk factors were considered, the
risk for major coronary events was lower among current users of hormone
therapy, including short-term users, compared with never-users (relative
risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated
estrogen, the risk for coronary events was similarly reduced in those
currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67])
and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0. 37 to 0.92])
compared with never-users. However, the risk for stroke was
statistically significantly increased among women taking 0.625 mg or
more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to
1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for >/=1.25 mg/d)
and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10
to 1.92]). Overall, little relation was observed between combination
hormone therapy and risk for cardiovascular disease (major coronary
heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]).
CONCLUSIONS: Postmenopausal hormone use appears to decrease risk for
major coronary events in women without previous heart disease.
Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with
a reduction similar to that seen with the standard dose of 0.625 mg.
However, estrogen at daily doses of 0.625 mg or greater and in
combination with progestin may increase risk for stroke.
Jeffrey Dach MD
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