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Statin Drugs Revisited by Jeffrey Dach MD

Posted Mar 27 2012 10:05am
Statin Drugs Revisited by Jeffrey Dach MD

Links and References

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. ====================================================

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.

==============================

www.ncbi.nlm.nih.gov/pubmed/19263395

4. 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.

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Elderly

Krumholz HM, et al.
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

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

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

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

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. (I’m referring to the people who follow the strategies I advocate, not the guy who thinks that smoking a pack of cigarettes a day is still okay, or the woman who thinks the diet is unnecessary because she’s slender.) Two high-profile deaths from heart attacks occurred this week: Davy Jones–The iconic singer from the 1960s pop group, the Monkees, suffered sudden cardiac death after a large heart attack, just hours after experiencing chest pain. Andrew Breitbart–The conservative blogger and controversy-generating media personality suffered what was believed to be sudden cardiac death while walking. It’s a darn shame and it shouldn’t happen. 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

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 =========================================================

Primary Prevention of Heart Disease With Statins

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 V6T 1Z3 Office +1 604-822-0700

Two important questions regarding statin therapy are: What is the overall health impact when statins are prescribed for primary prevention? Should the dose of statin be titrated to achieve target lipid levels?

Three new randomized controlled trials1-3, which help answer the first question and one trial providing insight into the second question have been published since our last Letter on lipid lowering therapy (#42). This Letter addresses the first question and the next Letter (#49) will address the second.

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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)

Safety Announcement

Additional Information for Patients

Additional Information for Healthcare

Professionals Data Summary

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.

Data Summary

Removal of routine monitoring of liver enzymes from drug labels FDA reviewed current monitoring guidelines, including the National Lipid Association’s Liver Expert Panel and Statin Safety Task Force recommendations.1, 2 The Liver Expert Panel stated that the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins. The Panel made this recommendation because

(1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and

(2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy. The Panel believed that routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy, thereby placing patients at increased risk for cardiovascular events.1

The National Lipid Association’s Statin Task Force also stated that routine monitoring of liver function tests is not supported by the available evidence.2

FDA reviewed post-marketing data to evaluate the risk of clinically serious hepatotoxicity associated with statins. FDA had conducted several post-marketing reviews of statins and hepatotoxicity between years 2000 and 2009 by searching the Agency’s Adverse Event Reporting System (AERS) database. Those reviews consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely low (reporting rate of ≤2 per one million patient-years).

FDA’s updated review focused on cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury Network (DILIN) liver injury severity scale, which were reported to AERS from marketing of each statin through 2009.

Cases meeting those criteria were further assessed for causality. Seventy-five cases (27 cases with a severity score of 4, and 48 cases with a severity score of 5 (37 deaths and 11 liver transplants) were assessed for causality. Thirty of the 75 cases (14 deaths, 7 liver transplantations, and 9 severe liver injury) were assessed as possibly or probably associated with statin therapy. No cases were assessed as highly likely or definitely associated with statin therapy. FDA concluded that, despite a rising use of statins as a class since the late 1990s, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use. FDA also reviewed cases from the DILIN and Acute Liver Failure Study Group (ALFSG), organizations that have been submitting reports to FDA of drug-associated liver injury in their liver injury outcome studies.

As of January 1, 2011, DILIN had submitted 25 reports of statin-associated liver injury to FDA, 12 of which gave hospitalization as an outcome. A 2010 article from ALFSG included 133 prospectively identified cases of idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and in six of these 15 individuals a statin was identified as the only potential drug to cause drug-induced liver injury. Based on all available data, FDA has determined that all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins.

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.

Subsequent to the June 2011 label revisions to the simvastatin-containing products, which were based largely on the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial,27 a review of drug-drug interactions with lovastatin was conducted because the physicochemical and pharmacokinetic properties of lovastatin are comparable to those of simvastatin. Lovastatin is a sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrate. Strong CYP3A4 inhibitors are predicted to significantly increase lovastatin exposure.

A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold and the drug interaction appears to result in rhabdomyolysis.28 The effect of itraconazole on lovastatin exposure can therefore be extrapolated to other strong CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, human immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, and nefazodone.

------------------------
Stephen Sinatra MD

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.

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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.

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Shane Ellison

cochiro.com/2010/05/20/the-cholesterol-conspiracy/

The Cholesterol Conspiracy By drshane on May 20th, 2010

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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*)

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CAC Coronary Calcium Scores and Statin Drugs

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

www.ncbi.nlm.nih.gov/pubmed/11473739?dopt=Abstract
Am J Cardiol. 2001 Jul 19;88(2A):16E-19E.

The development of calcium deposits in atherosclerotic lesions and their persistence after lipid regression. Stary HC. Source Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. hstay@lsuhsc.edu Abstract

Children have both macrophages and macrophages that are filled with lipid droplets (foam cells) at susceptible sites of arteries. Such changes are minimal and may not develop further. However, in some adolescents, small pools of dead foam cell remnants and lipid droplets (extracellular lipid) are added to the foam-cell accumulations at the susceptible sites. The pools are the precursor of a much larger confluent accumulation of extracellular lipids (the lipid core)-the hallmark of the atheromas of young adults. As soon as a lesion with a lipid core is present, calcium granules of microscopic size are found among the packed extracellular particles and droplets and in smooth-muscle cells isolated among them. Disintegration of arterial structure at the core facilitates tears at the surface, hematoma, and thrombosis. As a response, layers of reparative fibromuscular tissue are added and may predominate in a lesion. Over time, calcium lumps and plates form through accretion of adjacent extracellular calcium granules. In adults past the fourth decade of life, the greater part of the former lipid core of a lesion may be calcified and there may be osseous metaplasia.

The effect of therapeutic reduction of high levels of blood cholesterol on lesions was studied in rhesus monkeys. Drastic reduction of blood cholesterol levels for 312 years resulted in the disappearance of macrophages, macrophage foam cells and lymphocytes, and reduction of extracellular lipid from advanced lesions. Calcium deposits remained in the arterial wall and were not visibly changed.


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Baychol Intensive Statin Therapy reduces CAC

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.

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Statins Reduce CAC if LDL less than 120

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.

Abstract BACKGROUND:
Angiographic studies of the regression of coronary artery disease are invasive and costly, and they permit only limited assessment of changes in the extent of atherosclerotic disease. Electron-beam computed tomography (CT) is noninvasive and inexpensive. The entire coronary-artery tree can be studied during a single imaging session, and the volume of coronary calcification as quantified with this technique correlates closely with the total burden of atherosclerotic plaque.

METHODS: 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.

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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, New York 10003, USA. hhecht@aol.com

Abstract

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.

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Statins Reduced NON-Calcified Plaque Volume on CAT arteriography

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 (225 +/- 41 mg/dL vs. 162 +/- 37 mg/dL, P < 0.0001 and 148 +/- 7 mg/dL vs. 88 +/- 5 mg/dL, P < 0.001, respectively).

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 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. Using multislice detector computed tomography, physicians have the potential to monitor medical treatment in patients with coronary atherosclerosis.

-------------------------------------------------------
Very Significant !!!!

Progression of CAC in patients on Statins Predicts increased risk for MI

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

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

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   !!!!!

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.

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Statin therapy induced a 61% reduction in the rate of coronary calcium progression !!!


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.

---------------------------------------------

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.

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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.

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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.

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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.

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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

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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

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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.


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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




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Elderly - Propper - Provastatin Study

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). T reatment can 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

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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

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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.



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