Posts Tagged ‘Plavix’
Is Genetic Testing Useful After All?
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.
Add One More to the List
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.
Everything You Wanted to Know About Sex But Were Afraid to Ask
My apologies to Dr. David Reuben, who wrote the book by this title in 1971, for stealing his title. Yes it seems a long time ago that people thought this was so controversial. I guess that’s what the Internet has done. People are definitely more informed. Or are they?
It turns out that we cardiologists are not doing a very good job giving advice on resuming sexual activity after sustaining a myocardial infarction, and it seems we must do better. I must plead guilty as charged. I spend considerable time telling people to take Plavix and aspirin, and to increase their statin dose, but honestly, it never really occurred to me to tell people about sex.
A study known as TRIUMPH or Translational Research Investigating Underlying Disparities in Recovery from Acute Myocardial Infarction: Patients’ Health Status was presented at the recent American Heart Association meeting in Washington D.C. It is quite an eye opener. Only 46% of the men and 34% of the women received post discharge instruction when to resume sexual activity. Less than 40% of men and less than 20% of women had any discussion at all about sex with any of their physicians in the year after a heart attack.
The study found that 67% of men resumed sexual activity, but only 40% of women in that year. These data were controlled for variables such as age and partner status, so the reasons for the disparity is not that women were single or uninvolved more than men. It seems that there is significant room for improvement.
This lack of information clearly needs to be improved, and to become a greater focus of our discussion with patients. It may help to start a program with a trained health care professional who would take the lead in providing information and guidance with a doctor’s order. This is similar to other outreach programs that have been successful. Cardiac rehab may also serve as a place to provide this kind of information. Offices visits post hospitalization also seem like a place to start the conversation, as these areas are generally more private than a patient room or other hospital settings.
It’s time to help “Stella get her groove back.” It’s just one more example that we must care for the whole patient not just the lipid levels. Thanks to these researcher’s for pointing out an area of much needed improvement.
Initial Results in the Development of a New Antiplatelet Drug
An article was published in Am Heart J 2009:158:998-1004 that describes the results of the first trial of a new compound that is a P2Y12 inhibitor and that we are also working with at the Jim Moran Heart and Vascular Research Institute.
This compound known as elinogrel is the first P2Y12 compound to be both IV and PO. In other words, it can be given intravenously and then given by mouth. This is a large benefit because in emergencies, even if a loading dose of Plavix or Effient is given; it is several hours before the effect of the drug takes place. Even so the giving of the P2Y12 drug before angioplasty is clinically better than giving it after.
Having an intravenous compound that begins to work immediately may be a better alternative. This approach was attempted in the CHAMPION trials that we participated in but the study design was felt to be flawed. The drug did what it was supposed to but there was no clinical benefit.
The study published was ERASE-MI and it utilized four doses of the intravenous compound elinogrel and the loading dose of 600mg of clopidogrel. Patients then stayed on Plavix after the procedure. These patients were entered into the study because of an acute myocardial infarction. The study showed no differences between any dose of elinogrel and placebo when looking at laboratory values, corrected TIMI frame count, ST resolution of serious adverse events.
The study we did led by Dr. Joshua Purow was INNOVATE and it evaluated both, the intravenous and the oral forms of elinogrel. The enrollment is complete and we are awaiting the results, which will hopefully be available for the American Heart Association meeting in November.
We are proud to be part of this type of work, which we feel may improve the clinical outcome with patients who undergo angioplasty. Further work will need to be done on this compound before it reaches FDA approval and it would not be available for some years.
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.
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.
Compromising Combinations
As disturbing as it might be to me, it appears that the FDA does not read my blog. I have written several times about the controversy concerning the combination of the drugs Plavix and the proton pump inhibitors. I and many other more prominent and learned cardiologists than I thought the controversy was resolved by the publication of the articles mentioned in my last blog on the subject.On November 17 during the American Heart Association meeting in Orlando, the FDA issued a public health warning on the “possible interaction” between Plavix and one proton pump inhibitor Prilosec.
Apparently the FDA was not swayed by the data from COGENT which I have reviewed in previous blogs. Maybe they know something that we have not been told. They have required the manufacturers to update the label of Plavix. The “label” is that piece of folded up tissue paper that you sometimes get with new drug prescriptions that is written in micro type and reads like Greek.
It should be noted that although no other members of the proton pump inhibitor class were mentioned, the drugs that the FDA recommended to use with Plavix are the H2 antagonists such as Pepcid or Zantac. Tagamet cannot be used as it is metabolized the same pathway that Plavix is and will have the same consequences that the use of Prilosec will.
If you are taking Plavix and need help with the risk of GI bleeding your doctor will be the person to ask what you should do. The “safest” decision may be to take the H2 blockers mentioned and forget about it. If doctors other than your primary doctor or cardiologist try to put you on other medication, it is your responsibility to help us and tell us all the medications you are on. It is always a wise idea to check with your primary doctor when any changes are made to your medications.
I can guarantee you that this is not the last we have heard on this topic. I will continue this discussion as data is presented.
Look into Stent Options Before undergoing Catheterization
I will like to elaborate on a point I made in my last blog. I want to talk about the issue of patients who are undergoing cardiac catheterization for preoperative evaluation. These patients may or may not have evidence for cardiac disease either by stress testing or symptoms. What is done after the cath is critical and the need for non-cardiac surgery must be thoroughly discussed and analyzed before proceeding with any revascularization by stenting or coronary artery bypass surgery.
A study concerning this issue was just published in the journal Heart 2009; 95:1303-1308. It is titled Non-Cardiac Surgery and Antiplatelet Therapy Following Coronary Artery Stenting. This article reports a Meta analysis of this common clinical scenario. A Meta analysis is not a study. It is a statistical analysis of like studies that are melded together to seek out common similarities and differences in treatments. Although they often don’t fully answer questions, they point us in directions to ask better questions and can lead to meaningful dialogue.
This report covers 50,000 patients and finds that undergoing non-cardiac surgery while on low dose aspirin i.e. 81 mg. increases the risk of minor bleeding by 50%. There is no change in major bleeding except in prostate and neurosurgery procedures.
The use of Plavix during surgery increases the risk of major bleeding.
In previous blogs, I have discussed the use of these agents after stenting. If you have a non-drug stent, the current recommendations are to take aspirin and Plavix for a minimum of a month but if possible for one year. If you have a drug stent, the recommendation is to take aspirin and Plavix for one year. If you were stented for a myocardial infarction or unstable angina then the recommendations are one year regardless of what stent you have implanted.
In my patients depending on what type of surgery is needed, I often do not repair the coronary blockages until after surgery. Many operations can be done safely with aspirin and beta-blocking drugs such as Toprol and atenolol. There are many options but if not discussed this clinical scenario can lead to disaster. It is always necessary to thoroughly discuss all aspects of your medical condition with all your doctors.
Drugs for Life
As I have discussed before, one of the issues that we as Interventional Cardiologists deal with is how long Plavix should be taken with aspirin when patients have a drug eluting stent. The reason this problem is vexing is that these stents, and not “bare” metal or nondrug stents, can abruptly close; and when the stents do, it always causes a heart attack and can lead to death, in many cases. At the present time, the guidelines from the American College of Cardiology suggest that patients stay on aspirin and Plavix for a minimum of 12 months. Additionally, they feel the same way about bare metal stents. This is different than the original FDA guidelines which said that if you had a Cypher stent you needed three months of DAPT (dual antiplatet therapy) and if you had a Taxus stent you needed six months of DAPT. If you had a bare metal stent the recommendation was one month. It should be mentioned at this point that the expectation is aspirin for life.
I personally feel that all patients who have coronary disease and stents should stay on these drugs for life. I feel that they have a disease process that leads to further problems and will be benefited for the long term. Soon the cost will be lessened by the generic Plavix that we will see in 2011. At this juncture we have no data on what to do.
Recently, a study started funded by the device companies and Harvard to determine whether 30 months is better than one year of therapy. We will participate in this study. Patients will be asked to divide into two groups randomly. One group will take placebo after one year of Plavix and one will take Plavix continuously for 30 months. At the end of the study we will know if everyone should remain on Plavix. It will take nearly five years to do this study. This is what I have referred to as moving target medicine. Will anyone care? Will anyone still be on Plavix or will we have moved to one of the other Plavix like drugs of which there are already two others.
Next… the signals that long term Plavix may be best.
Is Your Medicine Making You Sick to your Stomach?
Gastrointestinal side effects such as reflux and bleeding are common in patients who take aspirin and Plavix. As I have written in other blogs, the effect of aspirin is local and systemic so that enteric coated aspirin does not lessen this risk. The importance of the drugs in preventing sudden coronary stent thrombosis led to the guideline recommendation that proton pump inhibitors be given along with aspirin and Plavix to lessen the risk.
Proton pump inhibitors such as Nexium and Protonix are drugs used to decrease the amount of acid in the stomach leading to a significant reduction in ulcers and reflux. They are used along with another class of drugs called H2 antagonists which are Zantac, Pepcid and Tagamet.
On May 6, 2009, a study was released at the Society for Cardiovascular Angiography and Interventions from researchers at Medco, a large pharmaceutical distributor. The study looked at the data from 16,690 patients and their conclusions were that instead of lowering the risk of major adverse cardiovascular events, this combination of drugs increased the risk from 17.9% to 25.1 %. Their data showed that all PPI’s were the same as far as risk of events.
As I have written before, this is the wonder and frustration of medicine. How can something which appears so logical be so wrong? Is it wrong? Why is it wrong? Researchers went to work to discover the problem. It seems that these drugs share a metabolic enzyme pathway and much like cars on a busy street, not all the traffic can travel at the same time. As Plavix needs to be metabolized, this interferes with the levels of the active drug, which in turn lessens the drug’s effectiveness.
But is it true? The Principle-TIMI 44 trial examined this problem and the study was released on line before publication. They found that no association was found between PPI use and increased risk for major cardiovascular events. This study used twice the normal dose of Plavix. In a similar study using twice the dose of Plavix (150mg a day), the PACA trial (Proton Pump Inhibitors and Clopidogrel Association) found that Protonix was better than Prilosec in preserving the necessary effect of Plavix.
What to do? I am recommending to my patients that if they must take these drugs they should increase the dose of Plavix. A better choice is probably to use the H2 blockers instead of these drugs for prophylaxis of GI bleeding. If PPI’s must be used, Protonix may be the best choice in the class. More information will be presented at the American Heart Association meeting in November. Individuals who are on these combinations should discuss this with their cardiologists.
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