New Reports On Statins
In the past few days much has been written about statins, and I would like to bring you up to date on these reports. Some show deficiencies and some show the promise and benefits of these amazing drugs.
Let’s start out by the report which admonishes us as doctors and you as possible patients. This report concerns the well known fact that many patients do not take their drugs in the prescribed way or not at all. This is particularly true when it comes to drugs that have a “potential” future benefit such as blood pressure meds and statins.
It is recommended that people who have a >20% risk of cardiovascular disease be placed on statins. As mentioned before, you can go to the risk calculator that I have referred to in previous blogs to calculate your own risk. I usually calculate the number when patients come to see me. By five years, the number of patients started on medication who still take it is approximately 50%.
Health organizations often consider lowering the threshold for treatment to treat more patients and lower the incident rates of disease. However, if you could increase the compliance to 75% of those that “need it,” more lives can be saved than if you just treat more patients.
How do you get better adherence to taking medication? No method has been tried in a randomized fashion. In today’s healthcare morass, it is becoming increasingly common for patients to see different practitioners each time they visit. I have found that a good understanding of why you are taking the medication helps but once the heart attack occurs you usually have patient’s attention. It’s the primary prevention patients that you want to capture and have them understand just how important it is to take this medication.
Having written the above, I will now tell you about a whole new group of patients that have been added to the “need statin” list.
Next…a new indication for Crestor.
Checking Up On the Doctor
I have often blogged about our guidelines. Guidelines are recommendations promulgated by my society, the American College of Cardiology, which are written by a committee made up of some of the most distinguished cardiologists today. The recommendations come from the research that is done and are powered into various groups with multiple large randomized trials, receiving the most weight and the strongest recommendation.
Over time these guidelines are adjusted as new information is developed and are not “secret” they can be viewed by anyone at the college’s web site at www.acc.org. They are not intended to replace patient-centered decision making by experienced clinicians. That being said it is interesting to see whether or not guidelines are being followed in certain areas.
The review chosen was my area of expertise cardiac catheterization and the choices made after cath; i.e. the recommendations for medical therapy, angioplasty or coronary bypass surgery based on the coronary anatomy identified. The study used the New York State Cardiac Diagnostic Catheterization database and was published in Circ 2009; 121: 267-275.
The findings were that 94% of those indicated for angioplasty received it. That 93% of the patients who needed bypass surgery or angioplasty, received angioplasty. However, in those patients that the guidelines indicated surgery, 53% had surgery and 34% received angioplasty. Of the patients that neither surgery nor angioplasty were indicated; 6% received surgery and 21% received angioplasty.
It seems that those of us with the “hammer,” the doctor, doing the cath often find the “nail,” the patient. These data don’t take into account the multiple other factors that come into play such as patient preference to not have surgery, status of the patients medical therapy and other co morbid issues, which may limit surgical options.
The group that received therapy when not indicated is the most troubling but a very small proportion of the total 10,333 patients in the study. What the study does show is that Interventional Cardiologists may be “growing the business” by pushing the limits of angioplasty. Many hospitals like Holy Cross have committees to review cases to help critique and improve the work done at the facility. I am proud of my profession in our ability to look at ourselves and present findings that may not reflect well on us. This is how we learn and continue to improve so we can perform in the best interests of our patients.
Just Stop… Smoking!
Let me start by saying that I have never smoked. I preface this blog with that statement because unlike many people and many of my patients, I have never had to quit smoking. I appreciate the struggle to deal with what used to be a socially accepted action and now, as we realize just how harmful it is smoking itself becomes less and less accepted. Even our President has been vocal in his attempt to quit and still struggles with it. His recent physical over the weekend again highlighted that he is still smoking intermittently.
Smoking is by far one of the most destructive things that human beings do to themselves. It truly is an act of self mutilation and it causes multiple problems. The risk of myocardial infarction increases with the number of cigarettes smoked. Cigarettes are the ultimate drug delivery device. The drug is nicotine and the smoke issue is a by product as are most of the carcinogens. They are now formally under the jurisdiction of the FDA but it remains to be seen exactly what that means.
Some facts:
In 2007 19.8% (43.4) adults smoked
Attempts to quit smoking decreased from 47% in 1993 to 48.8% in 2007
Only 4%to 7% of smokers trying to quit will eventually succeed
There is a 36% reduction in the crude relative risk of mortality in those smokers that stop
This benefit starts within one year and continues to become more powerful over time
The best way to stop is not to start. It is imperative that we focus education in young people so that they never start smoking. Cessation activities include psychosocial and pharmacological or both combined. The pharmacological approach entails bupropion SR, which is Wellbutrin, an antidepressant, nicotine replacement therapy and varenicline which is Chantix.
Recently, another study with varenicline was published Circ 2010; 121:221-229. This study used a group of patients with cardiac disease who were still smoking. Those taking the drug did better than those that stopped and the drug group did better than placebo. At the end of a year 27.9% were not smoking in the drug group and in the control group 15.9% were not smoking. Wow, even in a study with considerable counseling and support people can not stop. By the way, people were not asked if they stopped they were tested, to all those out there who smoke we have blood tests that now prove it. 10% of the drug group stopped because of side effects but the number of psychiatric side effects were not greater in the drug group.
Clearly we need better ways to help these people. My patients tell me that “cold turkey” is the only way to go. Whatever means you take you must stop, for you and everyone you know who cares about you.
Maybe Your Mother Was Right
I’m not making this blog up. An article has been published in Circulation, one of our most difficult journals to get published in. This article in Circulation claims that watching television is killing us. If you want a copy, e-mail me and I will send you a PDF. You can also click on the Circulation word, and it will link you to the article.
The article titled Television Viewing Time and Mortality: The Australian Diabetes, Obesity and Lifestyle Study (AusDiab) evaluated the effect of sedentary behavior with mortality risk. In particular, they examined the relationship of prolonged television viewing and the risk of premature mortality. 8,800 people participated in the study; 3,846 men and 4,954 women. None of the individuals had a history of any cardiovascular disease. The participants entered the study during 1999 to 2000. All participants were examined and had blood tests. The study ended on November 16, 2006.
Three categories of time where created <2, >2 to<4 and>4h/d and were assessed for a period of a week. This was a combination of television or video and you had to be watching. It wasn’t that the television was on but you were doing other things.
Over the 6.6 years, a total of 284 deaths occurred. 87 or 31% were due to cardiovascular disease, 125 or 44% were due to cancer and 72% or 25% were “other”. Each 1-hour increment was found to be associated with an 11% increase in all cause mortality and an 18% increase in cardiovascular mortality. Here’s the bottom line, if you watched more than 4 hours a day you had a 46% increased risk of all cause mortality and a whopping 80% risk of cardiovascular mortality, which was independent of the traditional risk factors such as smoking, blood pressure, cholesterol and diet.
Don’t tell NBC, they are having enough trouble figuring out what to do with Jay Leno.
Why this is so? Maybe the association of eating “snacks” when we watch television, but the data is well done and points out a further reason that we need to change our habits. Further, television watching is only one sedentary activity we do. The total time of sedentary work and computer use adds considerably to the problem.
The solution is simple but often ignored. Get up and do something, anything.
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.
Do we have the COURAGE to change?
I have blogged about the COURAGE trial in the past and I frequently refer to many of the common misunderstandings that patients have regarding the various treatments for coronary artery disease. As I have often said, the treatment for coronary artery disease is medical and then when medical treatment fails to treat the symptoms adequately, and that varies from patient to patient, angioplasty and then coronary artery bypass surgery is called for, depending on the angiogram findings.
The COURAGE trial was published in the NEJM in 2007 and became a recent topic in the Wall Street Journal on February 11, 2010. Keith J Winstein writing in the WSJ suggests that cardiologists have not changed their practice to account for the COURAGE results and this has cost 5 billion wasted dollars. The total US healthcare system spends an estimated 15 billion dollars a year on stenting procedures.
Further, the article makes the point that neither Medicare nor private insurance companies have changed their payments in regard to this issue. This may change as time goes on.
One of the integral parts of this controversy is our (speaking as an Interventional cardiologist) inability to always determine that an individual lesion is important. Angiography at a cardiac catheterization is the “gold standard” to determine the extent of coronary artery disease but it does not provide a “functional test”. What is meant by this is, “does the lesion in the coronary artery provide a lack of blood flow to the distal cardiac muscle bed?” We have methods of determining this before the catheterization by nuclear stress testing and at the catheterization by fractional flow reserve which I have blogged about in the past. This component was not part of the COURAGE trial. This test can safely determine which lesions are “safe” to defer angioplasty in.
In my daily practice I am already impacted in my ability to treat people as I wish. I will not “name names” but many insurance companies routinely deny nuclear stress testing regardless of the reason for the test and make you appeal the decision. I often have to get on the phone and explain to someone why I’m ordering a test. Medications are changed for “cheaper “versions in spite of long term success for the individual patient ignoring the successful achievement of “goal” targets.
I have spent my professional life helping to develop guidelines for the treatment of the illnesses with which I deal. Medicine and health care are not linear fields, often its one step forward and two steps back. I firmly believe in the COURAGE trial results but it did not impact my practice because that it how I practiced before the trial. We need to continue to do these studies and then incorporate them into our daily practice. The time will soon be here that patients will be better served by us by adhering to “state of the art guidelines.”
High Dose Statin Better
Old studies never die, they just get better. As published in JACC 54:2009:2290-5 Dr C. Michael Gibson (who is a member of our Scientific Advisory board) is the lead author of an article regarding PCI-PROVE IT a study that we participated in.
This study evaluated what happened to those patients that had an angioplasty and then were given either high dose statin in the form of Lipitor 80mgs day or lower dose statin in the form of pravastatin 40mgs day.
It showed that patients receiving high dose atorvastatin (Lipitor) had a significant reduction in adverse cardiovascular events when compared with a moderate dose statin. The end points in this study were all cause mortality, myocardial infarction, unstable angina leading to rehospitalization, revascularization after thirty days and stroke. This reduction is 22% above the benefit of the comparison of statins vs. placebo in other trials. Most interesting this benefit did not extend to the less than one third of the patients who were treated medically in the trial.
Why do high dose statins provide a better benefit? This is not entirely due to the lowering of lipid to an LDL of 70. That is the goal level in patients that have either angioplasty or coronary bypass surgery. The effect is referred to as “pleiotropic” and the effects are thought to include a reduction in inflammation (as in Crestor’s new approval for use in “normal” cholesterol levels with high CRP levels), plaque stability and the improvement of endothelial function.
Perhaps the most interesting finding is that this effect takes place within 30 days and then persists throughout the use of the medication. There is no “fall off’ of the effect and the group of patients who do not take the high dose can not “catch up.”
What this means is that after angioplasty patients should take the highest dose of statin for the maximal benefit. This has been shown in other studies also. This concept is difficult to get across to both patients and insurance companies. The insurance companies are constantly trying to switch my patients to a cheaper statin after I have achieved goal LDL levels. Further, patients are not used to the concept of more is better with drugs.
It appears that at least in Lipitor’s case the 80mg dose may fit everyone the best
What does PLATO give us?
The FDA recently received the submission for a new drug ticagrelor for the treatment of Acute Coronary Syndrome. As mentioned before, this syndrome is a significant cause of death in the United States. One in three who suffers from it will have death or another myocardial infarction within a year. Its effective treatment is vital to our war on cardiovascular death and disability.
Ticagrelor is an oral reversible direct acting inhibitor of the P2Y12 platelet activation site. This sentence tells you much about the difference between this drug and the other two agents; clopidogrel and prasugrel. Ticagrelor is reversible and they are not and this drug is a direct action agent and it is not metabolized into the effective agent so it has no biologic variability as clopidogrel does.
Ticagrelor was tested against clopidogrel in 18,624 who had acute coronary syndrome with and without ST segment elevation. The Plavix group received a 300mg loading dose (the standard at the time the study was done) and then 75mgs a day for one year. The ticagrelor group received a 180mg loading dose and then 90mg twice a day.
At twelve months the primary endpoint which was death from vascular causes, myocardial infarction or stroke had occurred in 9.8% of the ticagrelor group and 11.7% of the clopidogrel group. This yielded a statistically significant result P<0.001. No differences were found in rates of major bleeding 11.6% vs. 11.2% but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting 4.55 vs.3.8%.
This result is different from that of prasugrel, which had better outcomes but at the expense of more bleeding episodes. This likely stems from the fact that it is better metabolized that Plavix and so “more effective.” Another “good and bad” feature is that the effect on the platelet is short lived and that is why it must be taken twice a day.
It remains to be seen if patients will accommodate that. In general, most patients in my experience like once-a-day drugs. This drug is twice-a-day and “missing” it may lead to more stent thrombosis in general practice. Often patients are more “compliant” in studies and don’t live with the real world problems of obtaining their drugs by seeing the doctor or having to deal with Insurance companies that want to change from one drug to another.
This compound does give us the ability to change from Plavix to Brilinta in those patients who will require surgery and allow us to “load” patients in the Emergency room. Over all this is an advance in the treatment of coronary disease. I am sure that next will be a member of this class that is once a day. Slowly but surely we are improving the outcomes of patients with acute coronary syndrome.
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.
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