One More Weapon Against the Platelet
As I have discussed, the use of Plavix in patients with coronary artery disease is a complex and somewhat vexing problem. Plavix has been a useful drug and thankfully works in most patients most of the time. However, when it doesn’t work, patients are susceptible to stent thrombosis and further myocardial infarctions and even death that could possibly be avoided.
The problem derives from the lack of our ability to define who has an adequate Plavix platelet effect and who does not. We have what we call point of care testing but no studies have been conducted to define whether if you use the data and change the dose do you get the effect you want or does it cause harm.
Further, Plavix has one glaring both good and bad property. Plavix is irreversible so that once you have the drug active; it does not stop and must be “worn off.” This takes five days in the case of Plavix. The good news is that if you miss a dose, it doesn’t really matter, but if you need to get rid of the effect you can’t. You come into the Emergency Room with chest pain and our guidelines say you should be immediately loaded with Plavix. One hour later, you have a cardiac cath and need coronary artery bypass surgery. Now you have to wait five days before the surgery or risk receiving many more blood transfusions than you would need on average.
Two new drugs are on the horizon. One is here and one is coming. The new drug now available is Effient. I have blogged about this compound on August 10th and 16th.
Prasugrel (Effient) is another P2Y12 inhibitor that is also irreversible; however, it has a much more predictable effect than clopidogrel, so it is more effective than Plavix in providing a better outcome. However, the cost is that it causes more bleeding than Plavix especially in petite elderly females, so you have to be careful in patient selection. It needs to be “worn off” and delays surgery five days unless the surgery can not be postponed.
Coming soon is a third P2Y12 inhibitor, which is a different class of drugs from the first two. This drug is known as ticagrelor and will be known as Brilinta and was submitted to the FDA on November 19, 2009 for approval. It should be available by the end of this year. It was submitted based upon the study PLATO and that will be my next blog.
One Drug That Didn’t Make it…
It’s not often that the FDA turns down a drug. It is more frequent that a drug does not get an expanded indication from its initial indication for use. This is important because we as physicians can use any drug we want even if it is “off label.” The “label” is that piece of indecipherable paper that used to come with many drugs, but now has been relegated to the internet in lieu of preprinted information sheets.
Some drugs are used off label simply because no one wants to do the study and the use is already common in practice. Some are used off label because the study is being done and we don’t want to wait. Probably 75% or more of coronary drug stent use is “off label,” as the patients that we treat are not similar to the patients in the studies used to approve the drugs.
The reasons that drugs are restudied after approval are that the drug reps who come to our offices can only talk about those uses for the drugs or stents that are tested and “indicated” even though more use may occur off label. An example is the drug Provigil, which was approved for a very minor indication. Its use soared when it became apparent that an effect of the drug was that it heightened concentration to allow people to stay up longer, and did not have the same side effects as other Neuro stimulants.
On January 13, 2010, the Cardiovascular and Renal Drugs Advisory Committee turned down adding a heart failure indication to nebivolol, a drug approved in the US for the treatment of hypertension. The vote was 8-0 against it and the drug had already been denied by the FDA. An aside…although the FDA has final say on which drugs and devices are approved, they rely on a panel of distinguished physicians to help guide them. It is rare that a drug is turned down by the FDA that has been approved by the panel. Sometimes the panel itself is a source of controversy if the participants are not upfront about their ties to industry.
This drug is approved for its use in heart failure in 71 countries. Exactly what it was turned down for here and what happened here will be discussed in my next blog.
Will Cardiac Diagnostics Work?
We, as physicians, are used to measuring things. We measure temperature, blood pressure, height and weight. We measure your blood counts and the level of cholesterol in your blood. We are used to measuring things and part of this derives from the science of medicine.
In general, we believe that it you can measure something you will understand something better and possibly begin to change it. With the development of blood glucose monitors, we are able to be more precise in our control of diabetes. Those of you who are old enough will remember when glucose control was measured by urine test strips. Glucose monitors are now an essential part of diabetic care and are approved by Medicare and Insurance companies. There is some debate as to whether this glucose control does any real good but it is accepted by both physicians and the public.
How do you measure a hearts function. It is not blood pressure because a normal heart can have a blood pressure of 90/60; a failing heart can have a blood pressure of 200/110. The physical signs are rapid weight gain and special sounds we hear in the lungs called rales, which is derived from the French word rattle. A Frenchman Rene Laennec in 1816 developed the first stethoscope, again to measure something.
We measure heart function by measuring the pressure in the heart and lungs. I do this daily at cardiac cath and we have exquisite knowledge about these dynamics. We can also measure the pressures non-invasively by echocardiogram.
In the late 1960’s, two physicians at Cedars-Sinai in Los Angeles developed a catheter that could be placed in a vein and threaded into the heart to measure the pressures in the lungs. Initially known as a Swan-Ganz catheter after its inventors, Jeremy Swan and William Ganz, it eventually became known as a Swan. (Don’t ever be the second name on an invention.) These catheters saved millions of lives and led to an era of improved intensive care. The seminal article was published in the New England Journal of Medicine in August 1970.
We now have two ways that I know of to measure the status of the heart on a day to day basis. The science of these measurements is well understood. FDA before approval of the devices and the measurements demanded proof that the obtaining of the measurements led to good clinical outcomes such as staying out of the hospital with heart failure. We at the Jim Moran Heart and Vascular Institute participated in one of the device approval trials.
Next…the devices and why they may help us better care for patients.
Many Changes Bring the Hope of Better Care for Heart Failure
In my last blog, I discussed our abysmal record in treating heart failure. A great deal of effort is being directed to this health care challenge as it represents a great economic opportunity. The opportunity is on both sides of the equation with biomedical and drug companies on one side, hospitals and provider organizations on the other.
Medicare is relaxing some of the antitrust and Stark rules that govern the interaction between hospitals and doctors to allow for pilot projects that allow the division of money that is saved between participants. This topic alone is the subject of many very large books and I can not do it justice.
In brief, the projects allow for the joining of divergent groups to participate in clinical practice that is accountable for outcomes. In other words, you just can’t save money by denying care; you have to save money by doing it better. This process will allow for innovation to flourish, and let’s face it, innovation does better if there is reward at the end of it. All sides will be winners the hospitals will not lose as much money, practitioners will be compensated and patients won’t end up in the endless and damaging spiral of repeated admissions and hopefully will achieve a better quality of life.
Some of the biomedical companies have provided unique tools for our use and are now in the approval phase of them. The approval of these devices is interesting in itself. Since the devices do what they say they do i.e. measure something and that is not at issue the FDA requires that the “measuring” has some clinical benefit. To that end studies have been set up to determine whether by measuring “something” patients can obtain better treatment, have a better quality of life, and stay out of the hospital.
Now we as practitioners use a patient’s daily weight as a measure of whether a patient is stable in their condition. The increase in a patient’s weight signals a worsening of their condition and the need for intervention. That seemed pretty reasonable until it was shown that the weight gain comes 10-14 days after the worsening of the condition begins, so not only is it delayed but almost to late when it arrives.
In my next series of blogs I will detail the innovation that the medical industry is bringing to the problem.
Health Care Reform and the Treatment of Heart Disease
There have been endless hours of discussion regarding “Health Care Reform.” I once heard that you didn’t want to see sausage being made, but it sure tasted good. That certainly holds true for our process in Washington. Unfortunately, what the Congress and Senate are arguing about is not “Health Care Reform” but insurance reform and how we pay for our medical care, which as it is often pointed out, is very technical and expensive but it often doesn’t accomplish much.
Recently this phenomenon was again pointed out to me in an unsettling way. An article was published in Circulation: Heart Failure on November 10, 2009, detailing our United States failure in the treatment of heart failure.
This article detailed the startling fact that 25% of heart failure patients discharged were back in the hospital within 30 days. This was not occurring in isolated areas but was the figure across Medicare. Since Medicare recipients have insurance and drugs as well as ancillary care, the figure for non Medicare patients is likely higher.
Further, this readmission rate figure is consistent from year to year. It occurred in each of the years from 2004 to 2006. So not only are we doing a poor job; but we don’t even know how to fix it. This was documented by the statistic that half of the hospitals in the United States had risk standardized readmission rates within 1.5% of one another indicating that none of them had a better idea.
Part of the problem is that our present system rewards poor performance and stagnation. I do not mean that doctors don’t try to make a patient truly better from their chronic condition but if they “fail” and the patient is readmitted, they get paid again. If you had a car which didn’t work, how many times would you take it back to the same place to try again?
Although the problem can be identified in a blog, an entire book could be written on this issue. This is a major issue as it accounts for the major expense to the Medicare system. People do not realize that the mortality of patients with the diagnosis of congestive heart failure over five years is close to 100%. As heart disease is the leading cause of death in the United States, the amount of money being spent is truly astounding.
This is a topic I will blog about continuously this year. The medical system is moving on many fronts to confront and solve this problem and to define systems that work and can be put into place. Technology is now available to help and I will detail much of this in coming blogs.
Novel Future Treatments for Cholesterol
There are other novel and promising agents, which are being tested for the treatment of elevated cholesterol. One of the challenges I face on a weekly basis is that of patients who have coronary atherosclerosis and are on the maximum dose of statin and still have serious elevations of LDL cholesterol. We have no good treatment options at this time. These individuals try even strict diets to no avail. Many have a genetic condition referred to as heterozygous familial hypercholesterolemia which produces exceptionally high levels of LDL cholesterol.
One novel agent almost finished with testing is Mipomersen. This is a compound in development by Genzyme. Genzyme purchased the drug from ISIS Pharmaceuticals for $325 million and will pay a further $825 million if the annual revenue tops $5 billion in two consecutive years. To put that in perspective Lipitor had revenue of $16 billion last year and Plavix provides $11 billion in revenue to Bristol-Myers and Sanofi combined.
This compound is an antisense therapeutic agent. It is administered as a weekly injection and concentrates in the liver where the action occurs. It competes with the patient’s native compound and fools the messenger RNA which then decreases the production of apolipoprotein B thereby decreasing the level of LDL cholesterol.
Several studies have been performed and the pivotal trials are done. It is expecting approval late this year. It has been tested alone and in combination with statins and has been shown to be safe and effective. It is not clear whether the FDA will require clinical efficacy testing before release or after.
If effective this would become a useful compound in those patients who have not achieved goal with statins and in those patients who cannot take statins at all because of side effects. Novel treatments like this and ApoA-1 Milano may become the treatment of atherosclerosis in this decade.
And Away Goes Trouble Down the Drain…
In the middle ages, Alchemists dreamed of transmuting coal into gold. In much the same ways Cardiologists have dreamed of a substance that would remove plaque that had already formed akin to Drano removing scale and rust from pipes. The best we have so far is statins like Lipitor and Crestor, which has been shown to diminish plaque burden by Intravascular Ultrasound or as it is known IVUS. The mechanism by which statins work is believed to be more reorganization of plaque than the removal of material.
In June 2003 a study was published in JAMA 2003, which electrified the field of cardiology. Here was the promise fulfilled, a substance that would remove plaque. That substance is ApoA-1 Milano now called ETC-216 as it was purchased by Esperion and renamed.
Over the time period November2001 and March 2003, 123 participated in the study. All had ACS- acute coronary syndrome and I have blogged about this syndrome frequently. They were randomized into three groups’ placebo, low-dose and high-dose, and underwent once a week infusions of Apo for five weeks. IVUS was done before and after, and then analyzed to see the differences in plaque volume and composition.
The mean percent decrease was 1.06% in the treatment group and an increase of .14% in the control group. The absolute reduction in atheroma volume was 4.2% and this carried a p value of <.001. The lower the p value the more significant thus this is a very significant result.
In the short span of five weeks, atherosclerotic coronary lesions were shown to reverse. Further, the dose of ApoA-1 did not matter. Both the low-dose and high-dose had the same effect and it is believed that the mechanism of action is the stimulation of reverse cholesterol transport.
That’s were it ended. Since 2003 no further work was done because Esperion was purchased by Pfizer and Pfizer was probably doing that to “bury” it because it was working on its blockbuster oral drug torcetrapib. That failed and Pfizer said adios to cardiac research.
The Medicines Company has a track record of delivering new drugs to market that have not been adequately studied. Let’s hope that the work will now be started and finished to show whether this compound is the beginning of a new treatment strategy for atherosclerosis. I will keep you informed.
Good and Bad News on New Cholesterol Medications
We have a good news bad news situation. The bad news is that Pfizer once a powerhouse in the development of new cardiovascular compounds (remember Lipitor?) has all but removed itself from the field. The loss of close to one billion dollars on torcetrapib in clinical trials has given it a new course in research, one that apparently does not include cardiovascular diseases. Torcetrapib is a compound that raises HDL by up to 100% and had all of us itching to get our hands on. As I have blogged about before, the FDA now requires new drugs to show a clinical benefit and not just a chemical benefit. Torcetrapib did indeed raise HDL levels by 100% but in the process caused an excess of death in the treatment group, so it was pulled from development. Another drug in this new group known as cholesteryl-ester transfer protein inhibitors remains in study. It is known as anacetrapib and is presently completing its phase three study known as DEFINE.
What’s the good news? Pfizer had another drug in its research arm which is also full of promise. This compound is known as ApoA-1 Milano and has been known since the results of a small study were published in 2003. This compound has now been sold to The Medicines Company, which is the company that brought us Angiomax, the drug which is currently the preferred means of anticoagulation during angioplasty. The price will amount to $410 million dollars if milestones are met.
Why do we care about ApoA-1 Milano? It’s an interesting story that starts in the small northern Italian village of Limone sul Garda, a beautiful spot on Lake Garda, which is Italy’s largest lake. This town had no road until the mid 1930’s and before that was only accessible from the lake or by walking. In a town of 1,000 persons, over a dozen are over 100 years old. 45 of the townspeople were found to have a variant of apolipoprteinA-1 which is the main protein component of HDL. Their HDL levels are surprisingly low which also fed the mystery. It is from these types of discoveries that science advances. The work was started at the University of Milan and that is how the compound was named. The compound was then sold to a company called Esperion which was subsequently acquired by Pfizer and that is how we got to this point.
Next…why all the interest?
Erosion Pathology and Sudden Cardiac Death
I mentioned the clots that form in coronary arteries can be characterized as young or old in my previous blog. When someone dies suddenly from sudden cardiac death and they undergo an autopsy, if a clot is found, it can be analyzed and its age determined. Older thrombi defined as more than one day old were found more often and are believed to have a higher risk of death than thrombi less than one day old. Women were found to have older thrombi more often than men.
Dr. Virmani found that often a different type of pathology was found in sudden cardiac death — that of erosion of the lining of the artery which is made up of endothelial cells. This differs from the plaque-rupture scenario. Erosion pathology was found more often in women and it is speculated that this pathology which leads to older thrombus may be the reason for higher death rates in women than men.
In the study cited in my last blog, older thrombi were found in 79 of the 115 culprit plaques or 69%. In ruptures, the split was 50-50 between older and younger clots. In erosion pathology, 85% of the thrombus was older than one day. Further it was found that in women less than 50 years of age, 80% of those studied had erosion pathology. This is also true of young men. In men under 40 years of age who die suddenly and are studied, 50% of the lesions are of the erosion pathology. After that, plaque rupture predominates.
It may be those young women who complain of chest discomfort that is not definable by testing may actually have this phenomenon which will be very difficult to diagnosis with today’s tools. Smoking and birth control pills may also increase this risk. Treatments may need to be tailored to women and young men to increase artery size by vasodilating drugs and better use of antiplatelet drugs. In addition, a C reactive protein lab may be a useful test to determine if inflammation is occurring. You will remember in a previous blog that Crestor was given to patients with normal cholesterol and high CRP and that they fared significantly better than those that took placebo. The FDA extended Crestor’s indication to these people. Crestor’s drug effect maybe preventing this erosion pathology from taking place and leading to myocardial infarction and sudden cardiac death.
We continue to learn and to form treatments. Coronary disease continues to be the leading cause of death in the US. We need to do better.
To Clot or not to Clot
A recent blog discussed the fact that clots cause myocardial syndromes. Stable clots induce STEMI and unstable or waxing and waning clots cause ACS or acute coronary syndrome. The differences between the unstable and stable clots are not fully understood but much of the difference is due to platelet activation and much of that activation is due to smoking.The question has now become why do the clots form? What does the inside of the artery look like and can these changes be predicted and prevented. I have blogged before that a large portion perhaps up to 40% of myocardial infarctions is not caused by severely diseased arteries. What I mean is the extent of blockage in these arteries is less than 50% of the lumen. It was believed that the arteries in the less severe disease states suffered from edge “cracking”. When the normal artery meets the abnormal plaque a fragile zone is created and under the right circumstances ruptures. This micro crack exposes the blood to abnormal components and the clotting cascade starts.
A well known phenomenon is that an individual with acute coronary syndrome will often have several plaques that look “angry” at cath and it can be difficult to know exactly which one to fix.
Dr. Renu Virmani is a cardiac pathologist and has spent her life looking at coronary arteries that have caused syndromes and death. Unfortunately, if she is looking at someone’s coronary arteries that patient has died from their problem. Someone kindly consented for an autopsy. This work has been invaluable in the everyday practice of cardiology as it has allowed us to learn and modify our techniques. She was among the first to recognize and characterize late stent thrombosis and to give us an understanding of the incomplete reendothelialization that occurs with drug stents and to help us understand that longer use of Plavix is warranted.
Published in J Am Coll Cardiol 2009;DOI:10.1016 a new study again points to our continued learning about the relationships of thrombus to plaque morphology.
Next…what we learned.
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