Sunday, February 17, 2008

ADVICE: Cholesterol: Heart Disease: Fact and Fiction.

Introduction:

Many of the readers of this blog have elevated levels of cholesterol. Though elevated cholesterol levels afflict many, many remain untreated or inappropriately treated. Physicians often are unaware of appropriate treatments, their decisions often guided by glossy ads from the pharmaceutical industry that stress the need to prescribe their products rather than detailing how they may best optimally be used.
Negative press about Vytorin ® has also confused many , they are skeptical of the benefits of the cholesterol lowering agents prescribed by their physicians.
Congress promises to subpoena Dr. Robert Jarvik, the pioneering researcher of the artificial heart to question his bona fides and financial arrangements with Pfizer the manufacturer of Lipitor ®. The allegation is made that Dr Jarvik’s recommendation of Lipitor may be less than truthful driven by financial self gain.
He was paid in excess of a million dollars for his TV advertisements.
http://www.nytimes.com/2008/02/07/business/media/07jarvik.html?_r=1&hp=&pagewanted=print
http://www.nytimes.com/2008/02/08/business/media/08jarvik.html?_r=1&oref=slogin
Pfizer finally bowed to public opinion and pulled the Jarvik ads
http://www.nytimes.com/2008/02/26/business/26pfizer.html
This portion of the blog is lengthy.
It will attempt to define in language as divorced from science cholesterol and how this fat is responsible for heart attacks,
It will then detail the recommendations of reputable scientific bodies about how low the levels should be reduced for the preservation of health.
I have included a summary of the drug trials that have helped tailor these recommendations.
A section will also address the controversial role of diet and alcohol.

This blog has allowed me to post the source of the studies that I have summarized. For those inquisitive enough they can be explored but one may by ignoring them may more rapidly peruse the article.
For the impatient few they may rapidly scroll down and read the summary
The Cholesterol Factory





Once absorbed from food fats are transported to the liver. They are then processed and attached to transport proteins. There are two major transport proteins. Low Density Lipoproteins (LDL, or Bad Cholesterol) that transports cholesterol from the liver and deposits it in blood vessels reducing the diameter of these conduits. High Density Liporoteins (HDL, Good Cholesterol) so named as they help transport the LDL deposits back to the liver for reprocessing .


This obstruction of the blood vessels by LDL is thought to be central to disease of the blood vessel and the cause of heart attacks and strokes.

The many cholesterol lowering drugs.

Molecular Structure of Lovastatin

The statins (or HMG-CoA reductase inhibitors) form a class of drugs used to lower cholesterol levels in people with or at risk for heart disease. They lower cholesterol by inhibiting the enzyme HMG-CoA Reductase, that is present in the liver and is responsible for the formation of LDL. The first results can be seen after one week of use and the effect is maximal after four to six weeks. The levels of activity of this enzyme are to a major extent genetically determined.

Akiro Endo and Masao Kuroda Japanese chemists in 1971 were the discoverers of the class of drugs now referred to as the statins .The first agent isolated was Mevastatin (ML-236B), a molecule produced by a bacteria Penicillum Citrinum.

Scientists at Merck demonstrated an interest in this research and isolated a like compound Lovastatin (mevinolin, MK803, Mevacor), this was the first commercially marketed statin .

There have been several others brought to market since, Pravastatin (Pravachol), Atorvastatin (Lipitor), Fluvastatin (Lescol),Rosuvastatin (Crestor), Simvastatin (Zocor),) and the ill-fated now defunct Cerivastatin (Baycol).

They all share in common the ability to inhibit the HMG-Co-A reductase enzyme and thus reduce the formation of cholesterol. Their commercial sponsors make claims of the superiority of their products the claims and hype will be discussed in later segments of the blog. They also share the ability to cause liver and muscle damage in those susceptible

It was a plausible assumption that if the LDL producing activities of the cholesterol factory could be curbed that limitation of the supply of raw material (fat from food) from the intestine would further enhance the reduction of LDL.
Exetimibe (Zetia) was an agent that accomplished this. It blocked cholesterol absorption by blocking sites in the intestine where it was absorbed. While not as efficient as the statins in reducing LDL it did complement the statins causing additional reductions in LDL when used together with them.
Zetia was developed by researchers at Schering-Plough. It was co-marketed with Merck who further exploited this agent by combining it with their statin Zocor (Simvastatin). The combination was called Vytorin.
The superiority of this combination over the other statins was never demonstrated conclusively. Its development was spurred by a financial imperative. Merck was losing the patent protection for Zocor and it was hoped that this new combination would create a new patent protected financially profitable product. This combination did in fact reduce LDL levels more efficiently than the statins alone, however, despite this benefit it was not proved to be better in preventing plaque formation
In addition to cholesterol another related fat, triglycerides also contribute to plaque development. Triglycerides transport dietary fats in the blood and their increased levels are injurious to the blood vessels.
Levels of triglyceride are profoundly impacted by diet and exercise (reduction) and alcohol and diabetes (increase).There are medications that impact triglyceride levels Niacin is one that inhibits triglyceride production in the liver, it has the additional benefit of increasing HDL formation.
It is cheap but a limitation to its use is its propensity to cause flushing the susceptible user always feeling a sunburn. A sustained release form Niaspan is also available.
Fibrates another class of chemicals impede enzymes in the liver and muscle in the formation of triglycerides. They reduce LDL production less efficiently than the statins. They are believed to improve HDL production.Commercially available fibrates include Gemfibrozil (Lopid), and Fenofibrate (Tricor).
They may be used singly or together with the statins. Combination use increases risk for toxic effects of both drugs
How Does A Heart Attack Occur?
Cholesterol and other blood fats are deposited in the wall of a blood vessel (plaque) represented by the foamy deposits in the image below. They gradually progress in size reducing the size (lumen) of the blood vessel. The plaque can be compared to a dormant volcano, with bubbling lava (stable plaque)

The dormant plaque like a volcano ruptures and then wreaks havoc leading to the formation of a blood clot that obstructs the lumen of the blood vessel (thrombus) obstructing the blood vessel and limiting blood supply to vital organs like the heart and brain resulting in heart attacks and strokes.
The stable plaque becomes unstable with poorly controlled diabetes, smoking, excess LDL levels and as yet other unidentified factors.
Early destruction of the clot opens the vessel and restores flow. This simple description will serve as an explanation for the benefit of "clot busters", aspirin, angioplasty and stents for the treatment of acute obstruction


Statins and measures that reduce LDL are believed to reduce the size of the plaque and stabilize its contents
Images: (http://www.europa-trial.org/public/cad_what.asp)
A more dramatic representation of plaque rupture and vessel obstruction is illustrated by clicking the link below
http://www.medimagery.com/atherosclerotic.html
And....Back to Vytorin
Merck and Schering Plough the co-marketers of Vytorin® a medication used by many to reduce blood cholesterol would never have imagined that despite the large sums spent marketing the product a single negative report would spawn videos similar to the one that can be accessed by clicking on the link below.
http://www.newstarget.com/022501.html
This criticism is unwarranted and has ulterior motives. It is used as a marketing ploy to promote a “colon-cleanser” that would do much to rid the announcer of some of the hot air that he generates.

So Let Us Examine the Evidence.

Would Diet Alone Reduce Cholesterol to Ideal Levels?

An ideal approach to any human ill is self-discipline. If diet alone could reduce cholesterol to ideal levels it would be the prescription of choice. But self-discipline is a bitter pill unpalatable to many and acceptable to very few.

A report in the European Heart Journal (1997) vol.18, p18-22) examined the results of several studies relevant to diet and the prevention of heart disease and concluded
“The commonly-held belief that the best diet for the prevention of coronary heart disease is a low saturated fat, low cholesterol is not supported by the available evidence from clinical trials. In the primary prevention (prevention of heart attacks in patients with no prior history of heart disease), such diets do not reduce the risk of myocardial infarction (heart attack) or coronary or all cause mortality. …Similarly, diets focused exclusively on reduction of saturated fats and cholesterol are relatively ineffective for secondary prevention (prevention of repeat episodes in individuals with heart disease) and should be abandoned. There may be other effective diets for secondary prevention of coronary heart disease but these are not yet sufficiently well defined or adequately tested. The circumstantial evidence of benefit from oils, particularly olive oil, vegetables, fruit and fish is strong.”
Dr. Dean Ornish with almost messianic zeal has shown in limited populations that this conclusion is not true. His study that low fat diets could reverse coronary artery disease were proven objectively by demonstrating that individuals who followed a low-fat diet had not only a reduction in the deposits of fatty tissue (plaque) in the walls of the blood vessels but also a reduction in the number of heart attacks
http://www.ted.com/index.php/talks/view/id/10
(Intensive Lifestyle Changes for Reversal of Coronary Heart Disease. Journal of the American Medical Association . 1998;280:2001-2007.
http://jama.ama%20assn.org/cgi/content/full/280/23/2001?maxtoshow=&HITS=&hits=&RESULTFORMAT=&author1=dean+Ornish&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT )
His study was limited to very few subjects (less than 30 individuals) who were subjected to the low fat restrictions and the broad application of his diet to large populations is near impossible.Though a low fat diet should be recommended to all individuals for the prevention and treatment of heart disease its practical application in the real world of every day medicine is difficult and limited.
More recently the Atkins Diet has gained popularity or notoriety. It proposed dietary restraints opposite to those advocated by Ornish.It demonstrated that diets generous in fats and low in carbohydrates could result in considerable weight loss and in addition there was also an improvement in blood fat levels reported in the study accessed at the link below
http://www.annals.org/cgi/content/abstract/140/10/778?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Atkins+Diet&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT)
A comparison study between a low fat and a low carbohydrate diet published the same year noted the latter to be superior in weight and blood fat reduction. In addition it appeared to be more acceptable to those subjected to it
http://www.annals.org/cgi/content/abstract/140/10/769?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Atkins+Diet&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT)
An editorial that accompanied the publication of both these scientific studies suggested that there is no single diet that is palatable to all, that over-weight patients be allowed to experiment with different diets including those low in their carbohydrate content as long as the diets adopted incorporate healthy sources of fats and proteins. The dietary choice must be one that can be maintained rather than one designed for short term weight control
http://www.annals.org/cgi/content/full/140/10/836?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Atkins+Diet&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT)
Finally one cannot discount the value of exercise when combined with appropriate diets it more than complements them as related in the anecdote

Irish Diet
An Irishman was terribly overweight, so his doctor put him on a diet."I want you to eat regularly for 2 days, then skip a full day, and repeat this procedure for 2 weeks.
The next time I see you, you should have lost at least 5 pounds."When the Irishman returned, he shocked the doctor by having lost nearly 60 POUNDS!
"Why, that's amazing!" the doctor said, "Did you follow my instructions
The Irishman nodded..."I'll tell you though, by jaesuz, I t'aut I were going to drop dead on dat 3rd day."
"From hunger, you mean?""No, from f**kin' skippin", the Irishman said!!!

And if I should have to be treated how low should my cholesterol be??
There is a certain skepticism when recommendations are made for the long term use of a medication for a condition that at the time is not perceptible to the one being treated. The skepticism is justified. The less than exemplary behavior of the pharmaceutical in the Vioxx ® scandal is an example.
http://content.nejm.org/cgi/content/full/352/25/2576
Further a decision to treat is one that the subject in question will have to undertake life-long. In addition to the costs (considerable) the risks of adverse drug effects are ever present
Further a decision to treat is one that the subject in question will have to undertake life-long. In addition to the costs (considerable) the risks of adverse drug effects are ever present
There is also suspicion that the recommendations of medical experts are often tinged with financial links with pharmaceutical manufacturers
http://content.nejm.org/cgi/content/full/357/18/1796
This section will examine the process by which recommendations are determined for the treatment of elevated cholesterol levels.
The section immediately folowing it will describe the drug trials the results of which have shaped some of the recommendations.They will also address the conflict of interest.
In 1985 The National Heart Lung and Blood Institute launched the National Cholesterol Education Program (NCEP).This project sought to reduce the incidence of heart disease by education and reduction of blood cholesterol in vulnerable populations. It published recommendations in publications entitled the Adult Treatment Panels (ATP). Since its inception the NCEP has published three panels.
This blog will only address the third and most recent (ATP III) the recommendations in ATP III address those of the two previous and are the most recent.
http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf

ATP III lays particular stress on the following

1)Diabetics without CHD (coronary heart disease) should be treated with the same intensity as individuals with CHD. Such individuals are referred to as CHD equivalents.
2) An individual with more than 2+risk factors (age,male sex, family history, elevated blood pressure and diabetes in addition to elevated cholesterol are risk factors) must have their risk for future CHD evaluated.
If the individual is deemed to have a risk of excess of 10% of having a heart attack in the next 10 years this individual is a candidate for intensive treatment
Risk Assessment for CHD is easily accomplished by a web based tool that is freely avaliable to all and validated by the National Cholesterol Education Project.
http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=profit
Another interactive web based tool that suggests interventions after ones risk is calculated can be accessed at
http://www.cardiacriskcalculator.org/questions/gettingStarted
It was derived from results of the Framingham Study a study where the development of coronary heart disease was studied in a population over several decades.
Every individual with an elevated cholesterol can be risk stratified using the table
The results are expressed as a percentage likelihood of deveoping coronary heart disease in the next 10 years.
A percentile score under 10% denotes a low risk
Between 10 and 20% moderate risk
Above 20% high riskTreatment interventions are applied to the moderate and high risk populations as these are the populations most at risk and who would derive the greatest benefit from treatment.

Unfortunately risk assessment is not adequately used resulting in both under and over-treatment of this condition
To exemplify this a 40 year old female with a cholesterol level of 260mg% and an LDL of 140mg% will have a lesse risk of heart diseaase than a male of the same age who smokes and has diabetes. Treatment strategies have to be more aggressive for the latter individual
3)ATP III further identifies the metabolic syndrome as an indication for intensive treatment. The Metabolic Syndrome is identified by the following components that relate to CHD:
Abdominal obesity: given as waist circumference Men greater than 102 cm or 40 in. Women greater than 88 cm or 35 in
Triglycerides: greater than 150 mg
HDL cholesterol : less than 40mg%
Blood pressure >130 systolic/>85 diastolic mm Hg
Fasting glucose in excess of 110 mg
Further details on the metabolic syndrome are available at the link
http://circ.ahajournals.org/cgi/content/full/109/3/433
4)Identifies a LDL of less than 100mg% as the ideal for all populations
5)ATP III recommends a HDL level greater then 40mg%
6) Recommends treatment for triglyceride levels in excess of 200mg%
IN SUMMARY:
Desirable levels are
1) Total cholesterol less than 200mg%
2) LDL levels less than 100mg% for individuals withour heart disease and less than 70mg% in individuals with heart disease. This recommendations will be supported by drug trials discussed later
3) HDL levels in excess of 40mg%
4) Triglyceride levels less than 150mg%



Are these recommendations a ploy to sell pharmaceuticals?

This has been a charge leveled by some and a cursory evaluation of the financial relationships of some of the authors of the guidelines makes one pause:
ATP III Update 2004: Financial Disclosure
Dr. Grundy has received honoraria from Merck, Pfizer, Sankyo, Bayer, Merck/Schering-Plough, Kos, Abbott, Bristol-Myers Squibb, and AstraZeneca; he has received research grants from Merck, Abbott, and Glaxo Smith Kline.
Dr. Cleeman has no financial relationships to disclose.
Dr. Bairey Merz has received lecture honoraria from Pfizer, Merck, and Kos; she has served as a consultant for Pfizer, Bayer, and EHC (Merck); she has received unrestricted institutional grants for Continuing Medical Education from Pfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and Bristol-Myers Squibb Medical Imaging; she has received a research grant from Merck; she has stock in Boston Scientific, IVAX, Eli Lilly, Medtronic, Johnson & Johnson, SCIPIE Insurance, ATS Medical, and Biosite.
Dr. Brewer has received honoraria from AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/Schering-Plough, Fournier, Tularik, Esperion, and Novartis; he has served as a consultant for AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/Schering-Plough, Fournier, Tularik, Sankyo, and Novartis.
Dr. Clark has received honoraria for educational presentations from Abbott, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer; he has received grant/research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer.
Dr. Hunninghake has received honoraria for consulting and speakers bureau from AstraZeneca, Merck, Merck/Schering-Plough, and Pfizer, and for consulting from Kos; he has received research grants from AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, and Pfizer.
Dr. Pasternak has served as a speaker for Pfizer, Merck, Merck/Schering-Plough, Takeda, Kos, BMS-Sanofi, and Novartis; he has served as a consultant for Merck, Merck/Schering-Plough, Sanofi, Pfizer Health Solutions, Johnson & Johnson-Merck, and AstraZeneca.
Dr. Smith has received institutional research support from Merck; he has stock in Medtronic and Johnson & Johnson.
Dr. Stone has received honoraria for educational lectures from Abbott, AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, and Sankyo; he has served as a consultant for Abbott, Merck, Merck/Schering-Plough, Pfizer, and Reliant.
The National Heart, Lung and blood Institute is aware of these and handles these conflicts of interest in the following manner
Prospective members of the writing and review groups submit written Conflict of Interest/Disclosure Statements to an internal review panel considering their nomination and acceptance.The internal review panel considers conflicts of interest as a factor in the selection of nominees for writing and review groups.
Scientific and clinical expertise remains the paramount criteria for selection.
Members verbally disclose any potential conflicts of interest to each other during a general meeting.
A methodologist is hired to work with writing groups to provide objectivity in data analysis and ranking of evidence through the preparation of evidence tables and facilitating consensus.
There are then opportunities for public review and comments via the NHLBI Web Site and/or a scheduled public forum before the committee decisions are published and adopted into medical practice.
The researchers mentioned above are world renowned experts in the field of lipid medicine. Advances in the field would never occur if there not a commercial sponsor for the work and the likelihood of profit resulting from the research.
It is unlikely that the panelists would conspire for financial gain and their research efforts must be financially supported.
In the United States where there is reluctance to tax the public for scientific research private enterprise must provide such support, the development of drugs to counter cardiac disease must be credited to the pharmaceutical industry their profits come nowhere near the billions of dollars saved and the lives prolonged because of the use of these drugs.

Yes, these drugs lower cholesterol but do they prevent heart disease?




This question has been asked and answered by a process described as randomized clinical trials.
Here the efficacy of the drug in question is evaluated by its ability to prevent a clinical event. Participants in the study are assigned to drug treatment or placebo (dummy medication externally resembling he study drug) groups.To avoid bias they are randomly assigned using statistical tools.
Using this method the two groups have test subjects with similar characteristics (sex, age, cholesterol levels etc).
An end point is defined to prove the efficacy of the drug.
In the case of statins the ability to prevent heart attacks and death associated with heart disease is an endpoint by which the drugs are evaluated.
Similar studies have been performed comparing two statins.
End point studies can take several years to perform.
More recently to speeed up these studies endpoints used have been the measurement of plaque size by very sophisticated techniques.
These latter studies are limited by the fact that reduction in plaque size cannot always be assumed to be beneficial in the prevention of death from heart disease.
The studies are numerous and have exotic names some in keeping with a Star Wars generation a few of them are described below and the applicablity of their results to current treatment explained.
Scandinavian Simvastatin Survival Study (4S) (1994)
Demonstrated that subjects treated with Simvastatin (Zocor) had a 40% reduction in heart disease events when compared with populations receiving placebo alone
http://www.ncbi.nlm.nih.gov/pubmed/7572690?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.PubmedRVAbstractPlusDrugs1 This was the first proof that the statins not only reduced cholesterol but reduced the likelihood of heart disease in individuals using them.
West of Scotland Study. (1995)
demonstrated a 20% reduction in heart disease end points for pravastatin (Pravachol)
http://content.nejm.org/cgi/content/abstract/333/20/1301
This study implied that the protective effect of statins was not limited to a single product but was a class effect
CARE: The Cholesterol and Recurrent Events Trial (1996)
http://content.nejm.org/cgi/content/short/335/14/1001
Pravastatin reduced recurrent heart attacks in patients with normal cholesterol levels who had heart attacks prior to its use
This study proved that the statins had a beneficial effect in patients with heart disease who had normal cholesterol levels suggesting they had a protective effect in heart disease beyond just cholesterol reduction.
Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels: Results of
AFCAPS/TexCAPS (1998)
http://jama.ama-assn.org/cgi/content/abstract/279/20/1615?ijkey=b21204729e4ee359
Lovastatin (Mevacor) when given to a population with no symptoms of heart disease and average levels of cholesterol reduced their risk of an heart event by 30% over subjects treated with the placebo alone.
This study suggested that statins were capable of protecting individuals from heart related events even if the individuals were at average risk for such events
MIRACL: Myocardial Ischemia Rate Reduction with Aggressive Cholesterol Lowering. (2001)
http://jama.ama-assn.org/cgi/content/abstract/285/13/1711?ijkey=0cd78a8becc35f6d03fb305f1f7735d56bf76490&keytype2=tf_ipsecsha
Intensive treatment with high dose atorovastatin (Lipitor® ) after a heart attack reduced early recurrence of symptoms and need for repeat hospitalization.
Proof again that a stain was beneficial in patients even after they had a heart attack and prevented recurrent events
HPS: Heart Protection Study (2002)
http://www.ncbi.nlm.nih.gov/pubmed/15771782?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1 HPS enrolled 20,536 high-risk individuals and demonstrated that adding simvastatin to existing "best medicine" treatment produced additional benefits for these patients, irrespective of their initial cholesterol concentrations. It also demonstrated that the use of statins over long periods was not associated with the development of cancers
REVERSAL: Reversal of Atherosclerosis with Aggressive Lipid Lowering
http://jama.ama-assn.org/cgi/content/full/291/9/1071
A small trial (654 patients) that used a novel intravascular ultrasound (inserting a sound probe in a blood vessel to measure narrowing) assessment technique to demonstrate that even therapy with the 40 mg dose of pravastatin (Pravachol) that had proven efficacious in the CARE study did not stop the build up of plaque, whereas 80 mg of atorvastatin (Lipitor) halted, or even reversed progression
This is one of the few studies when one statin (Pravastatin, Pravachol ®) was compared with another (Atorvastatin, Lipitor®).
Before one draws conclusions and assumes that Atorvastatin is superior one has to read the fine print.
All the subjects in this trial had LDL cholesterol levels of approximately 150mg% at the inception of the trial. Due to differences in dosing Pravastatin (40mg) and Atorvastatin (80mg) those receiving the former had their levels reduced to 110mg% on average and those receiving Atorvastatin had average levels of 79mg%.
I do not believe that this trial conclusively proves the superiority of a single statin over any other rather it supports medical practice that lower LDL levels are more beneficial in plaque regression, Further this trial did not prove that despite plaque reduction there was any reduction indeth from heart attacks in those receiving intensive therapy.It does however provide clinical justification for reduction in LDL cholesterol to levels well below those recommended by ATP III in patients who had heart disease and are at increased risk of recurrent events


PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation: Thrombolysis in Myocardial Infarction 22 (2004)
https://content.nejm.org/cgi/content/abstract/350/15/1495
This trial compared "standard therapy" with 40 mg Pravastatin vs "intensive therapy" with 80 mg Atorvastatin in 4,162 recently hospitalized for a heart attack. Once again as in the REVERSAL study considerably greater reduction was obtained in LDL cholesterol with the use of the large doses of Atorvastatin. This larger decline in cholesterol with Atorvastatin was associated with a 16% reduction in death and re-hospitalization from another heart attack.
This study gave credence to the recommendations of the NCEP for aggressive treatment of LDL cholesterol especially in those with established heart disease

TNT: Treating to New Targets (2005)
http://content.nejm.org/cgi/content/abstract/352/14/1425
Designed to test "how low should we go?" this large trial enrolled 15,464 patients with established but stable heart disease and demonstrated the safety and efficacy of using 80 mg atorvastatin vs 10 mg of Atorvastatin to reach LDL cholesterol levels of 70 mg%
This trial supports the recommendations of several physicians that reductions in LDL to less than 70mg% be aimed for in patients with heart disease

ASTEROID: A Study to Evaluate the Effect of Rosuvastatin (Crestor®) on Intravascular-Derived Coronary Atheroma Burden (2006)
http://jama.ama-assn.org/cgi/content/full/295.13.jed60019v1
Using intravascular ultrasound high-dose statin therapy was been shown for possibly the first time to cause actual regression of plaque volume -- although this result is short-term and does not prove clinical benefit.
While the study did not prove any clinical benefit it did demonstrate that statins are effective in plaque stabilization

SPARCL: Stroke Prevention by Aggressive Reduction In Cholesterol Levels (2006)
http://www.ncbi.nlm.nih.gov/pubmed/16899775?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1
SPARCL was the first, trial designed to evaluate the effects of statin therapy in patients who previously had a stroke or transient ischemic attack (TIA) and who had no known heart disease Atorvastatin 80 mg/day significantly reduced the risk of recurrence in these patients.As well as bringing about a 16% reduction in the risk of stroke, the atorvastatin regimen also reduced the risk of major coronary events by 35%, coronary heart disease (CHD) events by 42%, and need for heart surgery by 45% in the SPARCL patients. A small increase in the incidence of hemorrhagic stroke(strokes with bleeding) wass noted.
This study was proof that since most strokes were associated with disease of the blood vessels statins were beneficial in their prevention and that they were effective in reduction of all events where an unstable plaque could be implicated.

METEOR: Effect of Rosuvastatin on carotid intima-media in low risk individuals with subclinical atherosclerosis (2007)
http://jama.ama-assn.org/cgi/content/abstract/297/12/1344
This study evaluated the effect of Rosuvastatin (Crestor ®) by measuring its effect on the deposition of plaque in the carotid artery (artery in the neck). The drug did reduce plaque deposition, but, did not reduce the volume of preexisting plaque. Its ability to prevent a heart attack was not proven in this study.
An editorial that accompanied the publication of this study cautioned that its results not be over- interpreted
Rather than pursue carotid artery imaging in asymptomatic individuals as is becoming a practice . Dr. Lauer from the Cleveland Clinic proposed
“And finally, where to go from here? Should low-risk individuals undergo routine arterial imaging followed by statin therapy when evidence of asymptomatic disease is discovered? On the basis of current evidence, including the METEOR trial, the answer is clearly no. However, like a shooting star in the night, the METEOR findings reflect a warning of problems lurking "out there" in the vast person-time space of the low-risk population. Epidemiological data have provided overwhelming evidence that low-risk populations are the source of most clinical disease.The METEOR investigators have now provided biological evidence for a plausible but unproved strategy.

http://cardiology.jwatch.org/cgi/content/full/2007/404/1

The Vytorin Saga
ENHANCE:
This study attempted to compare the combination of maximum dose of Zetia ® (Exetemibe)a drug that blocks absorption of cholesterol from the intestine combined with Zocor ® (Simvastatin) the combination called Vytorin® against the maximum dose of Zocor alone.
The study was done in individuals who were genetically prone to extremely high levels of LDL cholesterol. These individuals suffered from a condition called Heterozygous Familial Hypercholesterolemia.
The study measured thickening of the plaque in the carotid artery and the femoral (artery in the upper thigh) artery.
It was presumed that the combination would not only lower the LDL more efficiently but would also reduce the deposition of the plaque.
It did achieve the former goal but despite increased LDL reduction sophisticated arterial measurements did not show any improvement of the combination over Zocor alone.
In addition to the scientific benefit that positive results would have shown there was a commercial imperative. Zocor had lost its patent protection and if the study with Vytorin were positive it would enhance its commercial prospects.
This study was very sophisticated in its design and thus it took many months to analyze the results.
Andrew Cuomo the Attorney General from New York issued a subpoena alleging that the delay in reporting of results was a ploy by the manufacturers of Vytorin to mask bad news and continue sales
http://online.wsj.com/article/SB120137786357819747.html
Vytorin and Zetia had sales of $3.73 billion in the first nine months of 2007 and there declined 10% on news of the ENHANCE study.

Lessons Learned from the Vytorin (ENHANCE) debacle.
1) The reduction in the LDL is not always accompanied by equivalent reduction in cholesterol plaque
2) The fact that Zetia when combined with Zocor did no better that Zocor alone despite a greater reduction in LDL suggest that all drugs are not equal on plaque inhibition and there may be diffent methods by which they affect the plaque and the transport of cholesterol. This study seems to suggest that the effect of blocking cholesterol formation is not as profound as the inhition of its formation
3) This study showed NO adverse results of Vytorin use
4) The manufacturers are now studying 10,000 subjects in a study called … IMPROVE IT to try prove that despite the negative results of ENHANCE Vytorin is superior in preventing heart disease an end point we all aim for .

Finally

I have quoted a commentary form the Journal of the American Medical Association as I believe it is the most succint explanation of the competing interests of science and commerce.

http://jama.ama-assn.org/cgi/content/full/299/8/953

Lesson 1: Drug Trials Should Not Be Done for Marketing Purposes Only
Key questions about the ENHANCE trial include: What was this study designed to prove? How would the information be used once available? Would a "negative" outcome cause a different clinical impression than a "positive" outcome? Is it possible that the ENHANCE trial was designed for marketing purposes only?
First, it is unclear what the ENHANCE study was designed to prove. Specifically, a negative outcome most likely would not lead to a different clinical conclusion than a positive outcome, and it is unlikely that the ENHANCE results could have affected approval of ezetimibe by the FDA for any indication. Indeed, ENHANCE was begun at approximately the same time that ezetimibe received FDA approval for cholesterol lowering. Ezetimibe was approved in October 2002 while the fixed-dose combination of ezetimibe and simvastatin (known in the United States as Vytorin) was approved by the FDA in July 2004. ENHANCE was started in October 2002, and the last patient visit occurred in April 2006. A clinical end point study, known as IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin), was started in December 2004 and will not be available until approximately 2011, 9 years after FDA approval of ezetimibe as an adjunct to statins for cholesterol lowering. IMPROVE-IT is a multicenter, randomized, double-blind active comparator study that includes approximately 10 000 patients with acute coronary syndrome. Thus, data from ENHANCE and IMPROVE-IT will not affect FDA approval of these drugs for use in cholesterol lowering, unless significant unanticipated adverse events occur.
ENHANCE also was not conducted for the purpose of seeking a new drug indication—such as the role of ezetimibe in reducing cardiovascular events—because the study was readily acknowledged as underpowered for clinical end points, the only acceptable outcome for FDA approval of a new indication for these drugs.

Given these facts, one reasonable conclusion is that ENHANCE may have been undertaken primarily or exclusively as a marketing tool—with high expectations that the results would be positive and provide the company's sales force evidence of vascular benefit, even if not actual clinical benefit, to show physicians who were skeptical about the additive effect of ezetimibe combined with simvastatin. Indeed, some physicians have been critical of ezetimibe's clinical benefits for years,and the approval of Vytorin was predicted to initiate a major marketing battle in the cholesterol-lowering market due to the lack of clinical outcomes data for several of the new drugs in the market, including ezetimibe and rosuvastatin.
Further in support of the conclusion that the study was performed for marketing purposes is the fact that the study was completed in April 2006 but not reported in any form until January 2008. It seems that a much more immediate release of results would have accompanied the positive outcome that the sponsors expected. Late-breaking trial results, whether positive or negative, are always topics of major interest at cardiology meetings and in the peer-reviewed literature. Further, if the results are important for scientific reasons, they deserve to be reported as soon as possible. This issue has been widely discussed in the medical literature and has led to efforts such as routine clinical trials registration as a way of avoiding not reporting negative results. Given the circumstances surrounding this trial, the fallout for patients has been highly negative. It has provided an opportunity for much misinformation to circulate in the public media including articles questioning the entire validity of cholesterol lowering despite overwhelming evidence to support the concept as a cornerstone of cardiovascular disease prevention.
In summary, no result for the ENHANCE trial could have had any scientific or clinical importance, and the apparent delay in reporting the negative study results has raised additional concerns about the trial. If the drug company argues now in the face of negative or neutral results that a surrogate end point trial such as ENHANCE should not influence clinical practice negatively, it should be equally true that a positive result for the same type of outcome should have no positive effect on clinical medicine. In light of these facts, it appears that this trial was undertaken for marketing purposes only.
Trials designed for marketing purposes should not be conducted. Such trials divert attention and resources away from the critically important information needed from clinical end point studies, pose a serious risk to the integrity of the scientific process in clinical research, and may place patients at unnecessary risk. Physician-scientists must avoid the temptation to participate in trials that do not add to the science base in meaningful ways. Drug companies should stop conducting trials that cannot improve the state of science and cannot meaningfully add to the evidence base needed to make critical clinical decisions such as the choice of one drug over another for prevention of a clinical event. Many other similar studies are performed, and patients, physicians, and drug companies all stand to lose from studies that seem to be valuable only to drug company marketing efforts and only reported when the desired result is achieved.
Lesson 2: The News Media Must Be Sure to Get the Facts Straight. Errors in Reporting Can Cause Serious Damage, and Patients May Be Harmed or Become Distressed From the Resulting Confusion
The news media coverage of ENHANCE had several important factual errors. For instance, ENHANCE was a small-scale, surrogate end point trial, not a clinical end point trial. Yet, despite widespread claims to the contrary, nothing new (positive or negative) was learned about the prevention of clinical events through cholesterol lowering. The results were not negative—they were not statistically significant, or null. The end point was intimal-medial thickness, not "fatty plaque" as was misstated in some media reports. In addition, many experts cited by the news media appeared to be unaware of the actual results of the study because their statements reflected uncertainty, confusion, or incorrect assumptions.
Some newspapers published contradictory reports, confusing the public even more, whereas other sources extrapolated from this one study to paint the entire cholesterol hypothesis as wrong. In this case, the news media apparently fanned a lot of the frenzy and then seemed to stand back, unable to clear up the confusion or in some instances, added to the confusion. It is difficult to understand how such a study could mushroom in importance to the point that 50 years of serious and logical research has been damaged and defamed for no good purpose. The lesson is clear: the news media must be scrupulous and balanced in its search for factual information in medical studies and should be especially wary of results reported by companies via news releases. Likewise, medical professionals who are called on to comment on stories such as this one must carefully avoid creating confusion both by being well aware of the facts, and by not commenting without the availability of all of the relevant data.
Lesson 3: Leading Scientific, Patient-Oriented, and Disease-Oriented Organizations Must Scrupulously Avoid Conflict of Interest
In the aftermath of the release of the ENHANCE trial results, patients and physicians sought expert and unbiased advice about the trial. Both the American College of Cardiology (ACC)15 and the American Heart Association (AHA) issued statements with the goal of interpreting and explaining the incomplete and confusing results of this surrogate end point trial. These efforts, to some extent, backfired due to accusations of conflict of interest. An article with the harshest criticism indicated that the House Energy and Commerce Committee was investigating both the AHA and the ACC in regard to their relationships with Merck/Schering-Plough, but also reported that both organizations stated that industry financing, which they acknowledged having received, had "nothing to do with their statements."
Both organizations advise their volunteers and consultants to avoid conflict of interest and to report conflict of interest thoroughly. Writing groups for both organizations attempt to avoid conflict of interest wherever possible, and this is stated policy for both groups.
However, these steps are not enough, as the recent events show. These organizations must distance themselves from industry support to retain their credibility with physicians and health consumers. Without that level of credibility, the marketplace for truth is up for grabs, with no one capable of claiming the high road. As this issue has shown, a crack in the armor is capable of promoting an unwarranted reexamination of the entire topic of cholesterol lowering rather than only the pinpoint focus on a single study. Organizations such as the AHA must have credibility to advise the public in situations like this one and can only retain this credibility when there is not even a hint of conflict of interest

Well Which Statin Is The Best Statin??

The answer that every pharmaceutical manufacturers marketing and sales staff want to convince the prescribing physician is that their product is the best. The closest expression to liquid gold is the ink from a prescribing physicians pen.

Well has anyone examined the evidence, in fact they have.

Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 2006;151:273–81.

The authors compared the effectiveness of different statins for preventing cardiovascular events.Their analysis included eight placebo-controlled trials with 63,695 participants.
The authors evaluated randomised trials published between 1980 and 2004. To be eligible for inclusion, studies had to compare placebo or usual care with either pravastatin (5 trials), simvastatin (2 trials), or atorvastatin (3 trials) for long-term prevention of cardiovascular events; include cardiovascular diseases or death as an outcome; and include at least 1000 participants; and have at least one year of follow up.
The results:there was no significant difference between statins in reducing fatal coronary heart disease and non fatal heart attacksNor was there any significant difference in fatal and nonfatal strokes, all cardiovascular deaths, or all-cause mortality.
The authors concluded that, when used at standard doses, pravastatin, simvastatin, and atorvastatin appear equally effective for preventing cardiovascular events.

Well What About HDL? are there methods (drugs) to increase its levels?
Many believe that HDL which has been proven to carry LDL from the plaque to the liver where it is reutilized helps in the prevention of heart disease. For this reason HDL is referred to as “good cholesterol” levels less than 40mg% are thought to expose the individual to an increased risk of heart disease.

High concentrations in excess of 60mg% have been shown to be associated with a reduced incidence of heart disease.

The drug most effective in raising its levels is Niaspan. Niaspan is a derivative of nicotinic acid (VitB3). It has never been very popular as it has the ability to cause flushing in a large percentage of its users. Physicians tired of hearing of their patients’ therapeutic sunburns have resisted using the drug.
http://www.ncbi.nlm.nih.gov/pubmed/9915660?dopt=Abstract

More recently it has been recognized that combining it with a statin mitigates this effect. This observation has been commercially exploited in the development of a combination drug Simcor® by Abbott Laboratories.

The FDA has just released this drug for commercial use. On the day of its release the Wall Street Journal forecast that it would generate $500million in sales in its first year..Simcor is a combination of Simvastatin and Niaspan

The development of these agents is just beginning and the future will see many more of these hybrids
http://jama.ama-assn.org/cgi/content/abstract/298/7/786?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Niaspan&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
The real benefit of these hybrids is in the prevention of cardiovascular disease. But this yet remains unproven there is an inference that by raising levels of HDL while reducing those of LDL they will reduce heart disease further trials are needed to confirm this hypothesis. A recent publication has itself raised similar questions.
http://content.nejm.org/cgi/content/short/357/13/1301

One must view the current studies on HDL elevating drugs with some scientific skepticism. A digression examining a drug failure may be illustrative.
One of the chemicals involved in HDL synthesis is CETP (Cholesteryl Ester Transfer Protein).
The levels of CETP are genetically determined. The CETP gene is located on the sixteenth chromosome (16q21).
Rare mutations leading to increased function of CETP have been linked to accelerated heart disease.In contrast, a variant of the CETP gene leading to lower serum levels has also been linked to exceptional longevity. However, this mutation also increases the prevalence of coronary heart disease in patients with elevated triglycerides. Another genetic variation, which lowers CETP levels and increases HDL, also increases the incidence of heart disease confusing its role
http://content.nejm.org/cgi/content/abstract/323/18/1234?ijkey=cd21e78080650a7680a36ee7316a8a293d8665ca&keytype2=tf_ipsecsha
This genetic mumbo-jumbo is confusing and will illustrate and example of targeted and failed drug development for a drug to increase HDL.
Pfizer pharmaceuticals developed a new class of drugs to inhibit the CETP enzyme and thus lead to an increase in HDL levels. Toracetrapib was the name selected for their product.
Realizing that their financial block-buster Lipitor (Atorvastatin) would soon lose its patent protection they decided to combine it with toracetrapib.
The results of subsequent studies were a corporate nightmare.
The combination toracetrapib/atorvastatin did raise HDL dramatically when compared with atrovastatin alone but there were some other problems encountered.
Pfizer reported to the Food and Drug Administration, the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) study involving 15,000 patients at high risk for coronary heart disease was stopped prematurely, after a little more than a year, because of an excess of deaths, myocardial infarction, angina, revascularization procedures, and heart failure in patients receiving torcetrapib plus atorvastatin, as compared with those receiving atorvastatin alone.
This finding led some to postulate whether the result was a consequence of the mechanism of HDL increase or whether the drug itself was defective in an undefined manner.
http://atvb.ahajournals.org/cgi/content/full/27/2/257?ijkey=bdd9925f8c98aecccc22ab7aec1289bea4e11cb4&keytype2=tf_ipsecsha

A study measuring the rate of plaque progression in the two groups showed no difference despite a 60% increase in HDL levels with the combination and a 20% decrease in LDL. Observed was a slight increase in the systolic blood pressure of the combination subjects.
http://content.nejm.org/cgi/content/abstract/356/13/1304?ijkey=bab7ef9f14154f2da33196ed3cb84e2813bbea1a&keytype2=tf_ipsecsha
The message that we can derive from these observations is that HDL is a complex molecule with complex effects and though its increase is associated with a reduction in heart disease its role in the protection against heart disease is yet inadequately understood.

Is Alcohol the Vascular Drano ®?
"None seemed to think the injury arose from the use of a bad thing but from the abuse of a very good thing."
Abraham Lincoln.
Alcohol is regarded as a lubricant of social discourse. Before advocating its use one must realize that it is a contributor to many social and medical ills including liver disease, heart failure, hypertension to quote a few.
Alcohol does have a protective effect against coronary heart disease. Large scale studies have demonstrated that those who consume between one and two drinks a day have lower incidences of heart disease than non-imbibers.
Scientific publications have confirmed that moderate consumption of alcohol is associated with a reduction in heart disease a reduction paralleled by increases in HDL and its different factions.
http://content.nejm.org/cgi/content/short/329/25/1829
The harmful effects of alcohol on the heart occur primarily with heavy drinking and include dilated cardiomyopathy (weakening of heart muscle), heart rhythm disorders, and hypertensive heart disease. Alcohol can have opposite effects on the occurrence of stroke; it may promote brain hemorrhage, for instance, but protect against obstruction of blood vessels to the brain.
More recently an association between increasing incidence of cancer and alcohol consumption have been reported.
The only advice that one can offer a patient is that the risk must be individualized.
Regular consumption of relatively large amounts of alcohol -- that is, three or more drinks per day -- is undesirable from the standpoint of health for almost all people and that drinking low-to-moderate amounts can be desirable or undesirable, depending on individual characteristics.
Consider, for example, a 50-year-old man who is a moderate drinker. On average, he has a 20 percent chance of having heart disease and a 3 percent chance of having large-bowel cancer in the next 20 years. If his drinking reduces his risk of coronary heart disease by one third, even if it doubles his risk of large-bowel cancer, he would clearly come out ahead by drinking moderately. A known low risk of coronary heart disease and a high risk of large-bowel cancer. But a tendency to heavier drinking, or a history of operating an automobile or other potentially dangerous equipment after drinking could tip the balance in favor of abstinence
What about a 30-year-old woman who is a moderate drinker? Her risks of having coronary heart disease and breast or large-bowel cancer in the next 20 years are about 1 percent and 2 percent, respectively. Omitting her one drink per day would make these risks about 1.5 percent and 1.3 percent, respectively -- for a total that is virtually identical. On this basis only, health considerations would slightly favor not drinking. It appears that the risk of cancer is more important in the equation for young women than for middle-aged men.
Currently, indiscriminate advice to nondrinkers to take up alcohol for health reasons is inappropriate, but some people (e.g., those at high risk for coronary heart disease but low risk for problem drinking) may benefit.
Risks to health must also be weighed against the non-health-related benefits of alcohol. As in other areas of health care, the patient must, in conjunction with their physicians, make the final decision using a law that is forgotten that of common sense.

Well, which alcoholic beverage is the safest?

A scientific publication titled “Wine, Liquor, Beer and Mortality” attempts to answer this
http://aje.oxfordjournals.org/cgi/content/full/158/6/585?maxtoshow=&HITS=&hits=&RESULTFORMAT=&author1=Klatsky&fulltext=Doctor+Should+I+have+a+drink&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
The authors concluded that the frequency of wine drinking, but not of liquor was associated with a decreased cardiovascular mortality. There was no difference between red and white wines.
Further commentaries on a question whether abstinence from alcohol may be hazardous to one’s health may be perused by the interested
http://ije.oxfordjournals.org/cgi/content/full/30/4/739?maxtoshow=&HITS=&hits=&RESULTFORMAT=&author1=Klatsky&fulltext=Doctor+Should+I+have+a+drink&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
The relationship of alcohol to longevity is similarly explored
http://www.ajph.org/cgi/reprint/85/1/16


I Have Heart Disease, How Large Must Arterial Plaque be Before It is Dangerous?



Unfortunately atherosclerosis is not a discrete disease plaque is not small and restricted to one area of the vessel. Plaque is ubiquitous and present throughout the vessels in patients with atherosclerosis. The plaque in addition to its distribution also varies in size. Previous discussions of plaque described them as having a core of inflammatory material that like the lava in the volcano core bubbles but is dormant (stable plaque), there are also plaques where the process is more vigorous and the likelihood of rupture high (unstable plaque). When they rupture they initiate a clotting cascade forming a clot (thrombus) that obstructs the vessel preventing flow of blood to vital organs (heart , brain ). When these acute events occur with plaque rupture the ideal treatment is one of aggression to destroy the obstructing clot.

In these cases of plaque rupture or impending rupture aggressive intervention (angioplasty, stents, surgery and clot busting drugs) is the only effective therapy.
http://www.medimagery.com/atherosclerotic.html

Unfortunately these interventions are overused also in individuals with stable disease and no acute symptoms and where there is no life threatening need for intervention.
There is a wrongly held belief that the size of the plaque matters that the larger the plaque the more likely it is to obstruct blood vessels and rupture. This belief often propagated by the physician for personal gain is incorrect.
PLAQUE SIZE HAS NO RELATIONSHIP TO PLAQUE STABILITY
Plaques of lesser size have been proven to be more unstable than their larger brethren and more likely to rupture.
Thus repeated imaging studies by physicians to estimate plaque size and repeated interventions with catheters stents and the like in the stable patient are more beneficial for physician wealth than their patients health.
The downside to these unnecessary interventions and investigations aside from the cost is that they create a level of patient anxiety that often reduces patients to cardiac cripples and they ignore treatments that are of proven benefit and considerably less expensive. They also expose the patient to unneeded hazard
In an article entitled

"Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease" Circulation. 1995 Oct 15;92(8):2333-42. Steven Nissen and Eric Topol both past presidents of the American College of Cardiology stated

“Nearly 40 years after its invention, the angiogram is still considered by most physicians to be the "gold standard" for defining coronary anatomy. Careful investigations have revealed many deficiencies inherent in this approach. Angiography depicts coronary anatomy from a planar two-dimensional silhouette of the lumen. Angiography is limited in resolution to four or five line pairs per millimeter. Confounding factors include vessel tortuosity, overlap of structures, and the effects of lumen shape. After intervention, a hazy, broadened silhouette may overestimate the actual gain in lumen size. Studies show marked disparity between the apparent severity of lesions and their physiological effects. After myocardial infarction, cardiologists too often do not make an attempt to demonstrate the physiological significance of the stenosis before performing percutaneous coronary revascularization. Similarly, the allure of a better, more gratifying angiogram with new interventional devices appears to be a dominant factor in their popularity. Interventional cardiologists should be aware that techniques yielding marked angiographic benefit may also generate important but unrecognized hazards. The dissociation between the angiogram and clinical outcome should influence future research efforts. Our review of the literature indicates that we may benefit from shifting the current focus and preoccupation with coronary luminology to achieving the desired clinical end point: promoting survival and long-term freedom from myocardial infarction and the disabling symptoms of coronary artery disease.


The above illustration is one derived from a much respected cardiologist at Cedar Sinai in Los Angeles who decries current practices of dilating blood vessels (hole) where benefits are un proven while ignoring the cause for the narrowing (donut, plaque)
The investigation du jour is cardiac CT where the coronary narrowing can be evaluated non invasively. It has the same deficiencies as those detailed for angiograms by Nissen and Topol. Its widespread application is viewed with concern because of the increased risk of cancer with radiation exposure
http://content.nejm.org/cgi/content/full/357/22/2277

The authors concluded
"about one third of all CT scans are not justified by medical need, and it appears to be likely perhaps 20 million adults and, crucially, more than 1 million children per year in the United States are being irradiated unnecessarily"

Is there any objective evidence that angiograms, angioplasty, stents and the like are of litle benefit in the patient with coronary heart disease who has no symptoms?
This view has beeen examined and reported on

Optimal Medical Therapy with or without PCI (Percutaneous Intervention) for Stable Coronary Disease
New England J. Med. April 2007
http://content.nejm.org/cgi/content/abstract/356/15/1503

2287 patients who had objective evidence of significant coronary artery disease were followed at 50 U.S. and Canadian centers. Between 1999 and 2004, 1149 patients were asssigned to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal heart attacks during a follow-up period of 2.5 to 7.0 years.
There were no significant differences between the PCI group and the medical-therapy group in the occurrence of death, heart attacks and stroke, and hospitalizations for acute coronary syndrome (chest pain related to decreased blood supply to the heart) or heart attacks.

This and other unquoted studies are proof that in medicine the prescibers pen is more powerful that his scalpel.

IN SUMMARY:
1) Cholesterol is central to the propogation of heart disease.
2) It has two forms Low Density Lipoproteins (LDL or bad cholesterol) and High Density Lipoproteins (HDL or bad cholesterol)
3) LDL has been proven to create the plaque that obstructs blood vessels leading to disease of the heart and brain. HDL is believed to protect against the ill-effects of LDL though there is debate about its role.
4) A class of drugs (statins) by decreasing the formation of LDL reduce the formation of plaque in blood vessels.
5) The size of the plaque is not relevant unlesss the patient has symptoms
6) The plaque stability is important
7)An unstable plaque like a volcano may rupture and then a clot forms over it that obstructs the blood vessel causing damage to teh body organs downstream
8) Statins have been shown to reduce the levels of LDL. There has been a relationship demonstrated between the level of LDl and heart attacks
9) Statins also reduce plaque size but this effect has as yet not been proven in the prevention of heart disease
10) All statins are equal if used to reduce LDL to appropriate levels
11) It is recommended that total cholesterol levels be less than 200mg%, LDL levels less than 100mg% and in individuals with proven heart disease less than 70mg%. HDL levels above 50mg% are desirable as are triglyceride levels under 150mg%.
12) Alcohol use in moderation raises HDL its use must be individualized.
13) Aggresive interventions and investigations even in patients with coronary artery disease who have no symptoms have not been shown to be of benefit.
14) In like manner investigations to evaluate plaque growth in such patients is questionable.
15) The knowledge we possess is rudimentary and much more is needed to be learned.