For some time, the use of genetic testing has been heralded as the answer to many questions and problems that we face in the practice of medicine.  The reality has not gotten much traction, but genetic information may be coming of age.

As readers of my blog know, there is a difference between individuals in their response to the drug clopidogrel (Plavix) which can lead to serious difficulties and even death. As I have blogged in the past, it wasn’t until just recently that we as physicians had any idea that we were not getting what we paid for.   In the past, we as doctors had no choice because we had no drug option except to use it.  As I have blogged, two more drugs are now available and I have also blogged about them extensively.

This blog is about a report from the European Society of Cardiology meeting being held now in Stockholm, Sweden.  There is much heat, but not much fire about genetic testing for clopidogrel resistance and for platelet function testing to decide whether clopidogrel is working or not.  The researchers reporting the data from the large PLATO study comparing clopidogrel to prasugrel, shows that both prasugrel and ticagrelor the third agent which will soon be available, are not affected by the CYP2C19 gene or the ABCB1 gene.  In English this means that there is no variation in drug effect between patients and in effect you “get what you pay for”.

Theoretically, this kind of data would lead people to use these drugs over clopidogrel but the real world is different.  At this time, these drugs are basically the same price, but soon clopidogrel will be generic so we may be under pressure to use it.

One other factoid came to light during this discussion which I have wondered about.  It seems that when clopidogrel doesn’t work, it is almost always in the first 30 days and after that, the effect seems to have no medical significance.  So if you are taking Plavix and are doing well on it, you have no worries.

We as physicians will have to begin to understand these changes.  Just one more thing to remember.

For some time now, a compound known as mipomersen has been under development.  This compound, produced by the company Isis Pharmaceuticals in conjunction with Genzyme, is an antisense inhibitor of apolipoprotein B synthesis which causes a decrease in the LDL levels.  Antisense oligonucleotides are single strands of DNA or RNA that are complementary and prevent protein translation.  The drug will be an injection with an insulin type syringe that will be taken once a week.

It has received extensive testing in patients, who at maximally tolerated doses of statin, still do not achieve “goal”.  Not my beloved 35 mg/dl but,70 mg/dl.  None of these studies have been outcome studies, and it remains to be seen what the FDA will do with that issue.  Indeed, one disturbing side effect has been found. Liver enzyme elevations occur because the drug accumulates in the liver which is where all the “action” takes place anyway.

In one study,  58 patients with LDL levels of an average of 276 were given 200 mg/week for 26 weeks. There was a 36% reduction in these patients compared to those given placebo of 13%.

In a second study, when given with maximal dose statins in a patient population with a baseline of LDL 123 mg/dl, the effect of the drug lowered the average value to 70 mg/dl in over 50% of the patients.

This compound may be of great value to those patients who are doing everything in their power to drive their LDL down but a still unsuccessful.  Also there is a percentage of patients that do not tolerate statins in any dose who might benefit from this compound.

This is an example of new types of compounds that are coming forward to treat this illness.  In the future, I will again discuss a new class of compounds that may also help.  They are known as the CETP inhibitors.

In the Journal of the American College of Cardiology V. 56, No.8, several controversial articles were published relating to my recent blog about putting powdered Lipitor on Big Macs.  Specifically, they discuss the rationale for starting lipid lowering therapy very early in childhood to possibly prevent coronary atherosclerotic heart disease.

First, some interesting facts you might be interested in.  Guess what the LDL cholesterol level is when you are an infant?  Guess what the LDL level is in populations that are “rural” i.e. don’t have the “modern” diet that we eat?  The number is the same 35-70 mg/dl.  Why then do we permit the levels to be so high when we treat patients?  Why do doctors wait so long to treat?

A recent study the ASTERTOID, which was a study of carotid atherosclerosis, reduced LDL from 130mg/dl to 61mg/dl resulted in a lowering of the levels of atherosclerosis in carotid arteries as determined by IVUS.  A second study, the JUPITER, obtained a lowering of  LDL from 108 mg/dl to 55mg/dl in asymptomatic patients. This resulted in a 44% reduction in adverse cardiac events.  It could well be that the best LDL is closer to 35mg/dl than 70mg/dl.  Doctors will never get this.

Here is some genetic data.  There is a gene sequence PCSK9 which plays a role in the regulation of the expression of the LDL receptor.  If you have a mutation which causes this gene to not function properly you have a reduction of 28% which from birth leads to a reduction in cardiovascular risk of 88%.  On the other hand, if this gene up regulates, you have the same risk as someone with the genetic disease familial hypercholesterolemia.  This has already been seen in a population of African Americans that carry this mutation.

The ultimate goal would be a long term randomized study.  This will never be done even by the government.  In the 1960’s the NHI proposed a study to evaluate the role of dietary fat in cardiovascular disease.   They concluded that a five year study would need 50,000 to 100,000 men and consume the entire budget of the NIH for 5 years.  Can you imagine the cost now?

We may just have to agree to disagree —  and those that believe, will take large doses of statins and those that don’t believe, will not take the drugs.  I can honestly tell you that if you ask your doctor, and particularly ask your cardiologist,  they will tell you that they are on statins.

I will again point out (I’m starting to sound like my mother) that if we just ate better, much of this wouldn’t be necessary.  But, for the time being I will continue to urge my patients onward to a lower LDL.  It seems that it will have to be much lower.

The data shows that a Quarter Pounder contains 19 g of total fat and 1g of trans fat.  If you add cheese and a small milk shake you get 36g of total fat and 2.5 g of trans fat.  They don’t call it a “Whopper” for nothing.  The scientific data shows that by ingesting a dose of statin (except pravastatin), you can actually offset the “balance” of the meal.  The question — is this a valid way to eat?  Shouldn’t we eat better and take less medication?

It’s not just the trans fat and total fat.  The new target is removing all the salt from food.  Good luck with that.  How many years did it take for women to get the vote?  What good does it do if we take the salt out of the food if we just provide it back at the condiment counter?  That’s where the ketchup comes in.  Most people don’t realize the salt content of ketchup and how bad it is for you if you have hypertension, congestive heart failure (CHF) or coronary disease.

Diet is felt to affect cardiovascular risk in perhaps more than a dozen ways.  Clearly, it is involved with diabetes and the development of that condition.  Diabetes has a profound effect on coronary disease and coronary disease is right up there with renal failure as a mode of death in the diabetic patient.

It’s not just what we eat, it’s the amount.  I have blogged in the past about the effects of obesity on our population and the chaos it will soon cause in the healthcare system.  The majority of us just eat too much and we often don’t eat the right things.  The recommendation is to avoid processed foods, and try to eat as close to basic as possible.  This is the opposite of “fast food” although much has changed.  What has not changed is that when MacDonald’s offers us a choice of a salad or a Big Mac, we choose the Big Mac.  Taking a statin at that point is akin to buying a pack of cigarettes and getting an inhaler with it for your lung disease.

We need to be more proactive as to diet.  This is starting in school lunches and in some fast food establishments.  The “market” still wants the “bad” and I don’t see it changing soon.  Clearly, it seems to be getting worse.  We even have TV shows now like the Biggest Loser which highlights the losing of massive amounts of weight.  Wouldn’t it be better if you didn’t get that way in the first place?

There is not much excitement here.  If you have or want to prevent heart disease, you need to eat better - much better.  If after that, you still have elevated cholesterol you need to take statins IN ADDITION TO DIET.  If you have coronary disease, you need to eat better and take statins.

What is it going to take to get this message across?

On August 15, 2010 in the American Journal of Cardiology, a group of cardiologists reported on a concept and in doing so, unleashed a firestorm of controversy.  At first, lay people and physicians didn’t know if they were kidding and then became angry at the proposal.

What was this heresy?  These British cardiologists proposed that next to the ketchup, salt and mayonnaise at the condiment counter there should be a container of ground up statin that people would sprinkle on their burgers, and by doing so would alleviate the damage they were doing by eating the burger.

Where does one start discussing this?  First, I would like to note that in Great Britain you can buy a statin, Zocor (simvastatin), over the counter in doses of 10mg.   Much like you can buy Zantac here.  I applaud them for that. However, most of the science says that you need 20mg to obtain the benefit of simvastatin.  Again, I will mention that we believe the benefit is an anti inflammatory effect of the statin on the cholesterol. And that effect  lowers the of risk of further cardiac problems.

But where does the inflammatory effect come from?  Most people believe it comes from our diet.  There are some individuals that feel it comes from infection, but that line of investigation has not led us to any solutions.  It seems to be our diet.  Interesting sociologic data from many years ago, and you will have to excuse me because I cannot quote it exactly, shows that when you take the native Japanese population and move them closer to New York, the closer you get to New York, the higher incidence of heart disease you have.  Indeed, in any population of people who eat like us, the increase in coronary disease is noticeable.  The latest example is in China.

Come on people we are all basically the same genetic code.  How come we have such a high level of disease in New York but such a low level of disease in Africa? “It’s the diet, stupid”, to paraphrase a recent president who, by the way, lost a great deal of weight for his daughter’s wedding.  The genetic component of coronary disease seems to be the turning on and off of genes when they are exposed to a western diet full of all the things we love to eat.  This, coupled with cigarette smoking and high blood pressure, seems to be enough.

My 35 year old patient, with multi vessel disease, that I admitted after an anterior myocardial infarction says “hello”.  We are seeing this illness at a younger and younger age.

What are we to do…

This is not the end of the story.  We have a way to increase survival in sudden cardiac death.  Most people have seen the devices known as AED or automatic external defibrillators in public places.  The AED is a device, which when placed on a collapsed person’s chest, will automatically perform and allow the patient to survive 36% of the time.  Yes, the survival rate goes from 7% to 36%.

Here is a brief how-to if you are confronted with an individual that has collapsed.  First you must call for help and 911.  Immediately begin compressing the individual’s chest firmly and yes you might hear ribs or sternum breaking.  THIS IS OK and does not lead to problems.  Compress the chest firmly about 100 times a minute.  Send someone to find an AED and use it even if it means stopping chest compressions for a few moments.  Allow the AED to work over and over with intermittent chest compression until EMS arrives.  Know that you did the best you could and that the situation is bleak in the best of circumstances.  The outcome is not your fault.

A brief note - and maybe in the future I will blog about it further.  One of the challenges with the whole process is a patient that arrives at the hospital alive, but who is neurologically impaired by the brain not getting enough oxygen or blood.   We now have an evolving technique known as induced hypothermia which cools the brain down. This procedure is allowing improved neurologic survival in some patients.

Don’t give up.  CPR is fifty years old this year, and the entire concept and treatment of sudden cardiac death continues to evolve.  I don’t know how “Resusci-Annie” got her name, but she has taught an untold number of individuals who have stepped forward to learn CPR.  An estimated 295,000 individuals a year experience sudden cardiac death. You can understand the magnitude of the issue.  The number of deaths in this manner far surpasses all other diseases.  There will continue to be research in this area and we will continue to improve.  From 7% to 36% is a good start  - but only a start. 

One of the aspects of medicine and research that has always impressed me is the constant change.  We are very convinced as a group of people that this is the right drug or the right way to do things until someone points out our misunderstanding of the whole process.  This is very frustrating to the general public, but it reflects that there is often more than one RIGHT way to do something and sometimes it really doesn’t matter anyway.  It takes inquiring minds and people who think “outside the box”.

Remember at one time we were the people who brought you bleeding as a treatment for disease and drilling holes in heads to let the bad spirits out.  Things aren’t quite that bad today, but we arte still surrounded by good ideas that went wrong.  Dr. Gruentzig is an example of thinking outside the box.  He believed that you could work in the coronary arteries safely when everyone around him told him no.  If he did not persevere and make the original catheters by hand in his kitchen sink, angioplasty as we know it might never have happened.

Recently we were again given an example of this phenomenon.  Published in the N Engl J Med 2010; 363:434-442 is an article from Sweden that challenges a procedure that was thought to be correct.  That procedure is CPR or cardiopulmonary resuscitation and is the procedure used to resuscitate people from sudden cardiac death or collapse.  Since 1960, it has involved one or two people providing chest compression and mouth to mouth resuscitation.

Let me first say, that in the best of circumstances, this procedure is difficult.  Bystanders or family members who are called upon to help an individual who collapses are necessarily panic stricken.  Even in the hospital with trained personnel these procedures are difficult, frightening and emotionally charged and the outcomes poor.

It turns out that only using chest compression has the same results as the previous combining of mouth to mouth and chest compression.  Survival rates were the same.  I must now reveal the sadder truth which is that the survival rate at 30 days is only 8.7% in the group receiving compression only and 7.0% with the “standard therapy”.  Yes, sadly out of 1,276 patients only 100 survived and the neurologic status of those are not reported.

Next… there is a better way.

It is all but impossible to take a drug twice a day, and forgetaboutit if you want patients to take a drug three times a day.  This is possible, but it requires constant work. So in an effort to try to make it simpler, drugs are added together to improve compliance which in turn usually means their overall effect is better.

I have blogged in the past about the “polypill” which has been shown in Europe and India to benefit hypertension.  A “polypill” is a single drug which combines inexpensive i.e. generic drugs to make it easier to take.  Here in the United States we combine three expensive drugs and make it more expensive.  Go figure.

One such drug has now been tested and has been approved.  The drug Tribenzor is a combination of two generic drugs, hydrochlorothiazide and amlodipine and one non generic drug, olmesartan.  There is another of these drugs already approved known as Exforge and that is a combination of amlodipine/hydrochlorothiazide and valsartan. These drugs can be given separately and they will work the same. This is cheaper, but is it realistic?

I personally am waiting for the combination of Plavix, Lipitor, aspirin and Atenolol and people with coronary disease will be good to go.  One other problem with these drugs is that the combinations are fixed, and patients sometimes need different combinations to make the whole thing work.  Giving separate drugs makes this easier to do.

I am all for making drug therapy easier for people, but I think that it should be affordable for patients as well.  Drugs don’t work if you don’t take them and lately it’s a choice of food or drugs for many patients.  We have to do better as a country.  We are the worlds best at “rescue” medicine. If you bare desperately ill or injured, this is the place to be. But we lag seriously behind in chronic care preventive medicine such as for hypertension.  This is one reason why.

The third P2Y12 receptor antagonist was approved for release by the FDA Cardiovascular and Renal Drugs Advisory Committee and will certainly be approved for release by the FDA in the near future.  This drug is ticagrelor and will be known as Brillinta.

Why you ask do we need a third drug that does what Plavix does?  I cannot answer that question but there are 7.3 billion reasons to try in the market.  Yes, Plavix generates about 7.3 billion dollars a year which is split between Bristol Myers Squibb and Sanofi-Aventis.  It is the second largest drug sale worldwide.  Lilly which markets Effient is having a very hard time breaking into the market and that drug’s release has been a major disappointment.  For an “inside look” go to cafepharma.com which is an inside Pharma reps complaint board.  It makes for interesting reading.

The third entry may do better because it has an interesting property that distinguishes itself from Plavix and Effient.  That property is reversibility.  Plavix and Effient are not reversible.  That is why the drug takes 5 days to “washout” and there is a delay in surgery in patients previously taking the drugs.  The new drug Brillinta is not a thienopyridine it is a cyclopentyl-tiazolo-pyrimidine (CPTP) and as such needs to be taken twice a day.  If you miss two doses the effect is gone so patient understanding and compliance is essential.

Another interesting point is that there was an important difference in the study.  For reasons that are not clear but probably related to differences in aspirin use, the patients enrolled in the United States did worse then the patients enrolled worldwide.  Our aspirin dose was 325mg and the other dose was 100mg.   There is talk about labeling the drug so lower doses of aspirin are used.  At this point, no one knows and only post marketing data will allow us to figure it out.  This is not unusual.  It took nearly ten years to figure out that Plavix was not a “perfect” drug and that people respond differently to it.  At least this time we have a “heads up”.

It is not clear how the drug will be used and sometime next year Plavix will be generic.  When Plavix becomes generic it will not be “cheap” but it will be less expensive than the alternatives.  After more generics are allowed on the market much of the debate about the use of the drug will disappear.

Brillinta’s main use to patients maybe in transitioning patients off Plavix so they can go for non cardiac surgery or procedures such as colonoscopy.  There is no data on how to do this or whether it works or not but we will probably do it like we do other things  - learn by trying.  That’s why they call it the practice of medicine.  Some is science, much is art.

Erectile dysfunction has become another issue in patients with cardiovascular disease and risk factors and is fairly common in our society.  It is estimated that one in ten males suffer from it.  Its definition is the inability to develop or maintain an erection for satisfactory sexual performance.  This, of course, is subjective and varies from patient to patient.  It is also subjective from couple to couple; and I have had many discussions in my office with couples who are for or against the prescription of drug therapy for this problem.

Erectile dysfunction has been identified and treated as early as the 6th century, and in the past, required various devices or surgical procedures.  In 1983, a British physiologist injected himself with phentolamine producing the vasodilatation necessary for erection which heralded a shift in therapy to drugs. And then Viagra came along.

Sildenafil was synthesized in England and patented in 1996.  It is an inhibitor of cGMP specific phosphodiesterase type 5 and is responsible for vasodilatation of blood vessels.  It was thought to have potential as a treatment for hypertension and angina and was first tested on angina.  In Phase I trials for angina, it was found to have no effect on angina but a profound effect on producing erections.  The rest, as they say, is history.  Viagra was released to market in 1998 and annual sales exceed one billion dollars a year. 

Erectile dysfunction is often found in individuals who have hypertension, smoke and have high cholesterol. This also may be an early warning marker of advanced atherosclerosis.  It may become another “risk” factor for coronary disease.

The article relates that  patients who have erectile dysfunction and are depressed,  those with the most depression have the most cardiovascular events; and that depression is an independent factor in their problem.  The authors point is that if you are depressed, we as physicians need to find out if you have erectile dysfunction. And if you do, a higher degree of suspicion is warranted for the evaluation of cardiovascular disease.  The emphasis on treatment should also be greater and directed against the depression as well as the erectile dysfunction.

Does the depression give you erectile dysfunction or does erectile dysfunction give you depression?  Either way this probably goes beyond a locker room joke — although we may as men be fixated on these issues. The issues may well be an early warning sign of deeper problems.  If your partner has erectile dysfunction, it may be time to remove it from the bedroom and place it in the doctor’s office.