Posts Tagged ‘Coronary artery disease’
Do statins make you immortal?
My blogs over the past week have been concerned about the screening of asymptomatic patients for coronary artery disease and whether we make a difference in their morbidity and mortality if we find it.
That’s really all we are concerned with: Can we, as physicians, change a patient’s outcome by putting in place a medicine or a lifestyle? What good is it to find a problem if you can’t act on it?
To date, what we do when we find a patient who we believe to be at risk is tell them to stop smoking, control their blood pressure and their diabetes. And, we put them on statins. As those that read my blogs know, statins are our first line of defense against progression of coronary artery disease when a patient already has an infarct, angioplasty or coronary artery bypass surgery.
An article was published in Arch Intern Med 2010;170:1024-1031 which addresses this question. It is titled Statins and All-Cause Mortality in High -Risk Primary Prevention: A Meta-Analysis of 11 Randomized Controlled Trials involving 65,229 Participants.
This represents over 244,000 person- years of follow up. The average LDL cholesterol was 138 mg/dl and the results of giving statins yielded an average LDL of 94 mg/dl. An average of 3.7 years of follow up occurred in these studies and there was no evidence of benefit in these findings (7 fewer deaths for every 10,000 person years of treatment).
Although compelling, I believe that this study is flawed by the short follow up. Remember, this is not a randomized clinical trial which is the highest level of significance; it is a Meta-Analysis and only collates the data already collected in like studies.
Statins were approved because they were tested in randomized clinical trials against placebo and there was always a statistically significant reduction in a triple endpoint of unstable angina, myocardial infarction and death. Death however is usually the least affected because we are much better at preventing it if patients who are affected by an acute event present to hospitals. Patients who are found to be “at risk” will continue to be offered statins and the data shows that the lower the LDL is driven, the lower the vent rate. There seems to be no plateau. Every time a study drives the number lower, the event rate follows and some studies have the LDL as low as 50 mg/dl. The study known as TNT, or Treating to new targets,
showed this result in a study with over 10,000 patients.
The real study we want to do can not be done because it is not ethical anymore. Withholding statins from patients would never pass muster. It could be done in patients who refuse statins but the numbers would never be great enough. We will just have to accept the premise for the time being until science moves ahead of need.
What Does a Calcium Score Mean?
Technology now aids cardiologists in making decisions as to which patients may or may not have coronary artery disease. In the past, this was quite difficult and led to many needless tests and the repetition of tests that provided no value to patient care. As the readers of my blogs know, many pieces of a patients illness can be placed into risk calculators and then a risk can be assigned that will help cardiologists in decision making. The Framingham calculator is one such tool. The higher the score the more risk and the more concern with a work up. There is no one right way to do it.
It has become more and more difficult to do this without substantial interference from insurance companies. Many now require pre authorization before any work up and this includes cardiac cath. They are essentially practicing the medicine of NO. It is very complicated and time consuming to accomplish any sort of work up and this is likely to be the tip of the iceberg.
Now an article in the J AM COLL Cardiol 2010 55:1110-1117 has been published discussing the technique of calcium scoring and its usefulness in both determining who is at risk and when they would need to be tested again. As it is claimed in the article “what is the warranty for a negative score?”
When atherosclerosis starts in an artery, the artery first gets larger in a process known as positive remodeling. Only when this process stops does the obstructive phase of atherosclerosis begin so in general angina caused by blocked arteries is a very late phenomenon in the illness. Calcium is deposited and can be visualized in coronaries early on and this is what is seen on the CT scans. Using high speed scanners and one pass of the gantry a score can be assigned from zero to over a 1000. The higher the score
The more risk there is. If your score is zero, then you are likely to remain free of coronary events for four years according to the article.
This kind of work is useful for both determining the burden of illness and the limiting of downstream tests in an individual patient. It should in theory allow us to control costs in a meaningful way. That is if the insurance companies let us.
The End of Zetia?
We received news that the outcome study of ezetimibe or Zetia ,which is being performed under the name IMPROVE-IT, is slated to end in 2013. Data should then be available by the fall of 2014. Zetia’s patent expires in October 2016. Zetia earned Schering-Plough 1.9 billion dollars in 2006, and they split this money with Merck.
Let me put this in prospective. Two years before a multi-billion dollar drug undergoes patent release to generic, we will finally identify that the drug has some value beyond the lowering of a number. This is truly amazing when you think about it.
As I have blogged before in December 2009, this drug was approved on the basis of just the lowering of a chemical number and not that it reduces hard clinical endpoints. That is what this study is to determine. No one really cares if your LDL cholesterol number is lower just that fewer people die. Let me again point out that the reduction number does not need to be large just statistically significant.
There unfortunately are significant differences in that number and its meaning. Several blogs ago I discussed the new indication for Crestor. In the final analysis you have to treat 1000 patients to prevent two deaths using Crestor under its new indication. The number is significant statistically but is this indication really worth it to patients or just the company?
The issue was further clouded by the “lowering of the bar.” As Dr. Califf pointed out, (Note: I know Dr. Califf and he is one of the finest researchers in cardiology today) “because this study is done on a background of simvastatin the incremental absolute reduction in LDL is expected to be modest and as a result the anticipated absolute reduction in event rates will be modest also,” Am Heart J 2010. DOI: 10.1016
As pointed out in my previous blogs, the ARBITER 6-HALTS study findings were more valuable then these findings will be.
This goes back to the science of LDL cholesterol. It is clear that patients who have peripheral vascular disease, stroke or coronary artery disease should be on maximally tolerated statin doses for the largest effect. This goes for people who have reasonable levels of LDL reduction on small doses of drug because it is felt that some of these effects are “pleiotropic” or to put it another way “magical” and is not fully measurable. These include the decrease of the “inflammation” of the LDL.
We know at least that Zetia is not causing harm because the study was not stopped by the monitoring safety board at half way in the study. Whether it does any good and whether we can afford to pay for it as a society will be left to an answer probably at the American Heart meeting in November 2014. Stay tuned…
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.
Weighing Your Surgical Options
I have over the last several blogs pointed out how ideas, when they come to medicine, need to be rigorously tested. I want to travel back to the original question which is “who needs coronary bypass or angioplasty to manage their coronary artery disease?” It is important to remember as I have blogged before that management of this illness is medically based. Patients need to stop smoking, manage their cholesterol with statins and diet, exercise, control diabetes and high blood pressure. At times, it becomes necessary to provide revascularization because primarily chest pain or angina is life limiting. This means that your lifestyle is hindered. This equation is different for a 45 year old man than an 85 year old man and realistic goals need to be put in place.
Angioplasty can often be easily done but does not provide a mortality benefit or a prevention of myocardial infarction. It is a treatment of symptoms that do not respond to medical management. Surgery is much the same. However, if you have left main disease or poor heart function with three vessel disease you will live longer if you have bypass surgery instead of medical management alone.
The method of surgery should be discussed with your surgeon and depends on the placement of your arteries, and the condition of the segments needed for bypass targets and other technical concerns. Also important is the surgeon’s case level and whether he or she is comfortable with the procedures required.
The concept of “minimally invasive surgery” and robotic surgery is untested at this time and is purely a variation that requires a good hard look. It was widely felt that off pump surgery would be better but that is not the case. Robots are very expensive and it remains to be seen whether the whole idea is worth the trouble and expense.
One further point about the ROOBY study is that it again proved the point about getting a complete operation. What I mean by that is that all the vessels that need to be fixed need to be fixed. Although that sounds silly, angioplasty will often target only certain arteries and “manage” the others. Off pump did a poorer job of bypassing all the vessels needed. This approach leads to worse outcomes with increased need for reoperation, angina and death. As always you should have a thorough understanding of what is wrong and what your options are. If you don’t get the answers you need continue to ask until you do.
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