Ticagrelor has greater potency than prasugrel, and prasugrel is more “potent” than clopidogrel.  It is not surprising then that the highest incidence of bleeding in these study patients was found in the ticagrelor patients.  This risk of bleeding may be directly related to its greater efficacy, which in turn leads it to have a greater effect on preventing stent thrombosis and death.

Ticagrelor’s pivotal study is known as PLATO and is published in the N Engl J Med 2009; 361:2330-2341.  This study compared clopidogrel and ticagrelor in the setting of unstable angina or myocardial infarction.  The results showed that the risk of  death was reduced from 0.7% to 0.2%,  the risk of stent thrombosis was reduced from 0.6% to 0.2% and  the risk of bleeding was increased from 3.5% to 5.5% when the two drugs were compared.

Though small, these differences in efficacy are significant.  The difference in bleeding is not.  If the drug is better, why don’t doctors use it?

Let’s start with administration.  Patients take Plavix once a day and need to take Brilinta twice a day.  This alone is somewhat of a problem.  As is well documented, patients have a hard enough time remembering to take their medication at all, let alone twice a day.  Secondly, cost; Plavix at wholesale is $6.08 a day.  The wholesale price of Brilinta is $7.24 per day.  The price for Effient is $5.78.  This is not the price that patients pay, but it is the cost that the insurance companies pay.  The difference is often passed on to the patients in the form of higher co-pays.  It is impossible to predict how much a prescription costs, much like it is impossible to predict the cost of your airplane fare.  Everyone on the airplane pays a different price, and everyone on your block pays a different price for the same drug.  What is certain is that the acquisition cost of Brilinta is going to be higher than the other drugs.

Another problem arose from the findings of the study.  This study, like most others today, was carried out in the United States and Europe. There was an unusual difference in results that was found between the US and Europe sites, which has no explanation.  In the United Sates, we often use higher doses of aspirin than our European counterparts.  The FDA placed a special warning or Black Box on Brilinta stating that it can only be used with doses of aspirin less than 100 mg (our 81 mg “baby aspirin”) because the results of the trial were different depending on the dose of aspirin.  The higher the dose, the worse the results.

There’s more: we doctor’s are difficult to change.  We use what has worked in the past, and there has to be a really good reason to get us to change course.  In spite of what congress thinks, we don’t write for drugs because someone gave us a pen or brought us a cup off coffee.  We have to be educated because, unfortunately, given the 24-hour day most physicians don’t read my blog or much of anything else.

One last point: Plavix will be generic in May 2012.  This will most likely put the final nail in the coffin of the newer drugs in this class.  There will be times when the newer drugs are indicated, but likely doctors will have to fill out paperwork and answer questions for the insurance company to cough them up.

New drug development is crucial to moving the ball down the field of illness.  The drug Brilinta is a valuable compound in the proper patient.  It will not replace our use of Plavix.

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What if the drug company goes through the whole process and at the end bring their drug to market and no one cares?  After all that work, what if no one uses it?

Such may be the case with the drug ticagrelor, which in the United States is known as Brilinta.  Why the drug has three different names I could not tell you, but it does.  This drug has been available in the United States since July 2011, and recently, Dr. Michael Gibson of Harvard spoke to a publication and stated that in five months, only 1700 prescriptions had been written.  Say what?  Is it really possible?

As I have blogged about, when clopidogrel replaced ticlopidine, we Interventional Cardiologists couldn’t get the drug fast enough. The data set we used was not there.  Only a few hundred patients instead of the thousands that are used today.  We, doctors, didn’t care.  We hated ticlopidine so much that we would have used anything.  It just so happened that clopidogrel was also a great compound.  Until recently, we thought it was nigh on perfect.  That is incorrect, but it seems that it is more than “good enough.”
It, however, could be better in some situations.  One main difference between clopidogrel and the two new players in the market, Effient and Brilinta, seems to be in the area of myocardial infarction and unstable angina.  Angioplasty and stent implantation occurs the majority of time in the setting of stable angina.  In other words, patients have a problem, but it is not an acute problem.  In this setting, there is probably not an apparent difference in these drugs compared to clopidogrel.  I say probably because the drugs were not studied in that manner.  Stable angioplasty is generally so “safe” that the number of patients needed to be studied would be prohibitive.  Even in the setting of myocardial infarction and unstable angina, the numbers of participants in the studies generally top 20,000.

In the Acute Coronary Syndromes, such as myocardial infarction and unstable angina, the rate of stent thrombosis runs between 2-3% after the stent is put in, and the patients are started on clopidogrel.  Two independent studies ACUITY and HORIZON-AMI confirmed this.  When bad things happen to patients, we silly doctors tend to think that it’s the fault of the illness and not something that we the doctor did or didn’t do.

The studies that approved prasugrel and ticagrelor fully document the benefits of these drugs particularly in the syndromes of ACS. Why don’t we care?
Next…the facts of the matter.

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In any language the idea was good, rein in physician fees , but no one has the stomach to pull the trigger.  This is not because doctors have much clout.  We as a group actually have none.  We aren’t unionized, we don’t strike, we can’t agree amongst ourselves that 2+2=4.  No, the clout lies in you our patients.  When patients over 65 cannot see a physician because that physician doesn’t take Medicare, then you know what hits the fan.  I would hate to be in congressional offices when the phones start ringing March the 1st.  It gets worse.  People my age have been paying into Medicare all our working lives, and our expectation is that we would have Medicare as insurance when we reached 65.  This may not be the case at this point.

These people vote.  Seniors carry an enormous amount of clout, and they don’t care for people who mess with their stuff.  That is why Medicare has been referred to as the third rail of politics.  For those of you who don’t know, the third rail carries the electricity to run the subway.  If you touch it, you will die.  A committee is now hard at work trying to figure out a way out of this mess.  It is not easy at any point but now even harder because the payments are linked to the debt.

If the payment cuts don’t go into effect, the debt will rise by roughly 300 billion dollars.  This is where the main problem lies.  The whole SGR is an accounting gimmick to “balance the budget.” One of the ways being floated to “solve the problem” is to use “war savings” to eliminate the Medicare payment formula (NYT 02/06/12).  You have to love one accounting gimmick that will cancel another accounting gimmick.

Clearly, 20 people who are House and Senate negotiators cannot solve this problem.  In March 2007, a 236-page document was drafted by MEDPAC  (Medicare Payment Advisory Commission) regarding proposed solutions to the SGR. It is available at www.medpac.gov/documents/Mar07_SGR_mandated_report.pdf for those of you who don’t have much to do.  Many more such documents have been written.  Most of the professional societies like the American College of Cardiology have weighed in on the topic and proposed fixes.  These fixes usually benefit one group as opposed to another (see above 2+2 =4), so many are competing and only serve to confuse our representatives.

My prediction is one more patch.  Given the election this year and the general hatred in Washington, it is unlikely that a solution will arrive on the wings of angels.  It will take a mandate to sort it out or until the platform is on fire.

I wish it wasn’t this way.  It is uncomfortable to live with the specter of such payment cuts and the possible dismemberment of a reasonable program.  Many changes need to be made.  We as a people were smart enough to go to the moon.  We are smart enough to do anything.  We are smart enough to fix this.   We just don’t seem to have the will.

I don’t know why.

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Much of these events are caused by well-meaning people.  Some of these events are just not terribly well thought out.  One such event is the creation of the many-headed beast known as the SGR.  Although you have heard about it, I am sure you don’t understand the implications of it or how it came about.  Most doctors don’t.   Doctors only know that Medicare fees across the board will be reduced around 30% on March 1st.  You hear about it because it was one of the items that made up the debacle in Congress at the end of last year.  The Republicans in the House were forced to accept the Senate compromise on extending unemployment benefits, holding off on the SGR and extending the payroll tax cut.  Once again the cuts to physicians were deferred to February 29. How did physician Medicare fees end up at this point?  It’s not pretty.

Here is a short version of the story; short because you could easily write a book on this topic.  The story starts in 1989.  In that year, Medicare introduced a fee schedule to pay doctors.  Already this gets complicated because the Volume Performance Standards set up at the time were intended to address some of the issues in physician payments.  For instance, doctors in different parts of the country get paid different rates for the same work.  More importantly, the payments don’t reflect that one physician may spend two minutes, and the other may spend one hour for the same payment.  Quality, performance and results are not paid for.  It’s simply a formula.  I have blogged about this in the past.

It was recognized early on that the VPS did not meet the goals.  Let’s face it, you can call these actions anything you want, but in the end, what the government is trying to do is limit the payments to physicians in a way which does not harm patients, their access to care and is palatable for doctors.  We must as a country assume control of the cost of medical care in some form.

In 1997, the SGR was created in the Balanced Budget Act to replace the VPS.   SGR stands for sustainable growth rate.  I will provide the actual definition although it is in the language known as “governmentese.”  I will then try to explain it in English.  The formula for the SGR is the growth in input prices, plus the growth in Medicare fee for service enrollment, plus the growth in the volume of physician services per enrollee relative to the growth in the economy.  The target is the Gross Domestic Product.  The difference in the SGR target number vs. the GDP is then supposed to be added or subtracted to the payment to physicians to make it revenue neutral.

Whoops.

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In our fragmented health care system, often one physician may not know important information about the patient that would preclude the implantation of a new generator.  Often the patient and family may not be exact in their recall or may not have been told outright that the “spot” on their lung that is being worked up is surely a problem.  Sometimes patients and families are told but don’t quite grasp the situation.  Humans are very good at avoiding the bad things and embracing the good.  Doctor to doctor discussion is often inadequate to the need.  At times the implanting doctor just does it because he thinks the referring doctor has done the leg work, and it isn’t until the procedure is done that the real issues arise.

One other problem arises when doctors are forced to have end-of-life discussions with patients and families.  Many won’t do it, and like other issues I have raised in the blog, many can’t.  Not replacing the generator may cause a patient to die from sudden cardiac death.  Most physicians believe that this is preferable to a long drawn out death, but there is no one right answer, and it is not for us to decide how you want to die.  It takes time and discussion and help to arrive at a solution that is best for each individual patient and family.  No one size fits all.

The article proceeds to give recommendations on how we can start to improve our care in this regard.  These include a comprehensive medical exam and full discussion with all the patient’s doctors; talking to the patient and family about their wishes and goals and a society-based initiative to bring together guidelines for clinical and ethical aspects of generator replacement.  Studies should be put in place to determine if a distinction can be made for further risk assessment based on the previous use of the device.

We should do better.  We must do better.  We need to concentrate on doing something for the patient instead of to the patient.

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Photo from http://nlm.nih.gov

I am constantly looking for “ah ha” moments.  Sometimes when they hit me, I realize that I have “been there before” but not with the clarity that the moment deserved, so the importance was not crystal clear and defined.

When my daughter was seven years old, she had her appendix taken out.  When it was over, I asked her what she thought about the experience.  Well they don’t say “out of the mouths of babes” for nothing.  She told me that she was scared.  I asked her why and she said that the anesthesia doctor kept telling her that he was going to put her to sleep but never mentioned that he was going to wake her up.

It was like a lightning bolt hit me.  We as doctors just assume so much that is not understood by a seven-year-old or a 70-year-old. The entire thought must be expressed and understood.  The beginning and the end.

Published in the NEJM on January 26, 2012 (N Engl J Med 2012; 366:291-293) is just such an article.  Titled Time for a Change- A New Approach to ICD Replacement, the article makes it very clear that we have not completed the process.  We as cardiologists have made great progress in defining who gets an ICD in the first place.  The problem is what happens when the ICD needs replacement.

ICD (implanted cardiac defibrillators) are placed in patients who need protection from sudden cardiac death due to arrhythmias that would be lethal if left untreated.  Often, but not always, these patients have a poorly functioning heart with an ejection fraction of <35%, inspite of attempts to correct what can be corrected, time and medication.  The decisions we make are because of many randomized clinical trials that have shown that more patients survive when given the device than without it and when given medication.

The question raised in this article is what do we do with the roughly 25,000 patients each year who need a replacement generator.  When the battery on the ICD is depleted after approximately five years, the pocket is opened, and the battery enclosed in the generator package is replaced after the wires are tested.  Patients continue to receive improved technology in this manner.  The generators are smaller now than originally thanks to lithium ion batteries, but many are still mismatched to thin individuals, which clearly have a noticeable device in their shoulder area.

What happens to the patients who get a second device?  Do they always need them?  Five years is a long time in someone who has diminished heart function.  Is the patient’s quality of life acceptable?  Oddly enough, replacement ICD’s have never been subjected to the same scrutiny that initial implantations have been.  At $25,000 or more, you would think that Medicare would care, but the prevailing “wisdom” seems to be that if the patient has one, just replace it.

Next…how to start to fix this mess.

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photo from tampabay.com

Now let’s move from sound bites to full-fledged out-and-out incredible.  I will cop to the fact that I generally don’t watch TV and never commercials since I record everything I watch.  News I get from the sites that I read on the web.  When I want a laugh, I will watch some Fox “News” in the hospital.

The Food Channel is pure America.  It would be funny if it wasn’t so scary that these people are really eating all of this.  One guy tries to go to all the places where you have to eat 20 lb hamburgers and tries to match the records.

I spent 15 years eating southern cooking in Atlanta when I sojourned there during school and training.  It struck me as good, and at times, wholesome.  There are some southern dishes that I never did get, or eat.  Not that it’s not good, it just doesn’t jibe with my tastes.

For years, Paula Deen has been cooking and promoting a style of food which no one can sensibly consider good for you.  As I have often said, it’s not what you eat, it’s how much.  Clearly, with some of her recipes, if you just eat two bites you are okay but not if you eat it all day everyday and don’t exercise 20 hours of the day. Guess what?  She did.

I am sorry for her, but here is the problem.  When she developed type 2 diabetes, which means that she is not insulin dependent,  she did not say anything.  She just went on selling crack to crackheads.  It’s like you sell matches to an arsonist.  It’s really surreal if you think about it.  She had a recipe for a hamburger which used two glazed doughnuts as a bun.

I saved the best for last.  She only revealed that she had been a diabetic for three years after she signed a deal with the maker of the drug Victoza, Novo Nordisk.  She is now prominently featured at the top of their website.

Victoza is one of many drugs that are being used now for type 2 diabetes.  It is injectable and is not insulin.  What it does is basically make you stop eating faster, so that you begin to lose weight and have better control of your diabetes.  Only in America can we develop a drug to make you stop eating.  Do we as a nation have no willpower left?  Are we truly at the mercy of our stomachs?

Indeed, on her web site at Pauladeen.com, she is now claiming to make the same recipes but not as fat or with as much salt.  I guess she is skipping the doughnuts and going back to bread buns; maybe whole grain.

Frank Bruni is a columnist for the New York Times.  I first started following him when he was the chief restaurant critic for the Times: a very prestigious job.  I became more interested in him when I found out that as a child, he was obese.  He wrote a book about his ordeal titled Born Round. He had quite a bit to say about Ms. Deen (NYT, January 21,2012).  As he says, “this is a profound, unsettling act of withholding.”  Apparently the wages of sin is a TV show and a drug endorsement deal.

In the article, he also discussed how famous chefs (at least some of them) stay thin.  It seems they religiously workout to burn calories and eat a great deal of salad and chicken.  What a novel idea.

Be careful what you watch on TV.  Be careful what you eat.  We will not make as much money on our disease as Ms.Deen.  I wish her health and common sense.

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This is a constant problem with randomized clinical trials.  The sponsors want them to be as clean as can be, and this often excludes the very people who will eventually get the drug.  There is much more awareness of this at this point, and often, the FDA or other individuals will step in and adjust the entry criteria to make it as close to the real world as possible.

Although large, the study under which Pradaxa was approved (the RE-LY study) encompassed only 18,113 participants.  These patients were  reanalyzed, and in a paper published in Circulation 2012 (DOI: 10.1161/?CIRCULATION.111.055970) on January 3, 2012, all ischemic events were evaluated.  These included CABG, PCI, unstable angina, cardiac arrest, myocardial infarction and cardiac death.  What they found was at the Pradaxa dose of 110mg, there was 3.38 events/100 patient years, at the 150mg dose of Pradaxa there were 3.58 events/100 patient years, and warfarin had 3.60 events/100 patient years.  Remember that the 75 mg dose was made up by the FDA and has never been tested.  I have blogged about this in the past.

To add to this, the clinical benefit of Pradaxa was greater than warfarin.  The 110 mg dose had a clinical benefit of 7.34, the 150 mg dose was 7.1 and warfarin’s was 7.91.  The net clinical benefit was a composite of stroke, myocardial infarction, CV death, pulmonary embolism, systemic embolism or major bleeding.

So the data clearly shows that Pradaxa does cause myocardial infarctions in spite of what Channel 7 says.

Or does it…

Published at the same time, and separate from the above article, is a meta-analysis published in Arch Intern Med 2012 (DOI: 10.1001/archinternmed.2011.1666).  This article evaluated seven studies which used Pradaxa in a range of conditions that this drug is used outside of the United States.  In addition, this meta-analysis includes other compounds as controls besides warfarin.

Acknowledging these problems, this analysis shows that Pradaxa has a myocardial infarction rate of 1.19% versus the other agents, which has a myocardial infarction rate of 0.79%.  It should be pointed out that warfarin is better at protecting patients from heart attacks than aspirin, but it is too much of a hassle to use in large populations.

As Artie Johnson used to say, “Verrrry Interesting.” As is usually the case in medicine, ask one question and get many answers.  I am not concerned about an increase in heart attacks in my patients who are all on aspirin and statins to lower their LDL as low as it will go.  I believe that patients need to be well anti-coagulated in atrial fibrillation and that we as physicians often fail in that.  Patients often fail also.  We have to make it easier for everyone.

Pradaxa and the new drug Xarelto, which is taken once a day, provide a clear benefit to patients in atrial fibrillation.  This message should not be clouded for patients by the mass media.

Now…let’s talk about more than sound bites.  Let’s talk about reality TV and Paula Dean.

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A meta-analysis is not a study, but it can provide important information and hypothesis-generating work.  Randomized clinical trials can then be fashioned to prove or disprove the hypothesis.  The more alike the trials included in the analysis, the more valuable it becomes.

This meta-analysis analyzed 13 trials each with at least 1,000 patients who were divided into two arms that were identical and followed for at least a year.  91,410 patients were included in the analysis.  During the four-year followup, 4,278 patients or 4.6% developed diabetes.  2,226 patients were treated with statins and 2,052 with placebo.  The difference was 9%.  In English, I have to treat 255 patients with a statin for four years for one of them to develop diabetes.  Those 255 patients had 5.4 deaths or myocardial infarctions avoided in those four years.

Death, myocardial infarction reduction or diabetes?  You decide.  Now let me mention that thiazide diuretics, beta blockers and the beloved niacin all increase the risk of diabetes in patients taking them to some extent.

Let me close this portion of the blog with the following: patients who have had a cardiovascular event need statins regardless of what they do.  Patients who have moderate or high risk should be on statins and carefully followed to determine their glucose status.  Everyone needs to eat better and exercise more.

If you are at low risk, a study such as calcium scoring will determine your cholesterol burden, and patients should be placed on statin when appropriate.

That is the information beyond the sound bite.

Now, let’s address the sound bite contention that Pradaxa causes myocardial infarctions.  This discussion is also very complex, and when reduced to a sound bite, does not benefit anyone.

Some facts: When Pradaxa at 150 mg twice a day is compared to warfarin, embolic events are 1.11%/yr vs. 1.69%/yr.  Hemorrhagic stroke is 0.10%/yr vs 0.38%/yr.  Ischemic stroke is 0.92/yr vs 1.20%/yr.
Major bleeding is 3.11%/yr vs 3.36%/yr.  Death is 3.64/yr vs 4.13%/yr.  The reduction in mortality is approximately 10%. This data is what caused the FDA to approve the drug.

Added to this are warfarin’s very real problems.  I will not dwell on all of them here, but they include — and are not by any means limited to — only 55% of eligible patients who receive the drug for various reasons, and this number increases as patients get older.   When warfarin is used, it is often ineffective.  During the first year, warfarin is therapeutic 58% of the time.  The lack of adequate therapy is often due to patient non-compliance with dose and/or food or drug interactions. Warfarin is, however, inexpensive.

Does Pradaxa cause more myocardial infarctions?

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There is an adage in TV journalism that “if it bleeds, it leads.”  The more grotesque something can be made the better.  Partial truths in medicine do not count.  This is not Presidential politics.  Patients for some reason often make health decisions based upon what they hear on the news, or worse, what their friends tell them.

I blame doctors for most of this.  I believe that people would rather hear it from medical professionals, but not many of us will give them the time to explain complex topics simply.  Some doctors can’t, some doctors won’t.  As I have said before, it’s the major reason that I spend the time to write my blog.

I certainly have things to write about at this time.  I will start by explaining why statins don’t cause diabetes, and then I will move on to why Pradaxa does not cause heart attacks.  Finally, I will touch on Paula Dean and why as Soupy Sales used to say “people who live in glass houses shouldn’t throw stones.”

First, it is important to understand that randomized clinical trials test only the hypothesis that is being tested.  In the case of statins, the hypothesis is that if you take them, you have less of a risk for an ischemic event than if you do not.  The risk reduction increase with increasing doses of statin that decrease the level of LDL cholesterol.

This topic has been widely discussed and understood for some time among those of us who follow these sort of issues.  The report which engendered the current rash of news stories is possibly the worst of the studies to quote.  The study was published in the Arch Intern Med 2012 (DOI: 10.1001/archintermed.2011.625).  It reports results from the WHI or Women’s Health Initiative.  This study encompasses 153,840 postmenopausal women 50-79 years old.  Data was collected at baseline and year three, and the data is from 2005.

Only 7% of the women in this study were taking statins.  Of those taking statins, at baseline 71% developed an “increased risk” of diabetes.  After adjustment for “confounding variables” the risk was 48%. (My quotation marks)

First of all, the absolute numbers are not provided.  What is meant by that is the following example: Plavix was approved because it had a reduction of stroke risk by 20%.  What is not understood is that the risk of stroke in the control group was 1.8%.  The risk in the Plavix group was 1.3%.  This is a 20% reduction but you need to treat 200 patients to get one benefit.  The largest use of Plavix, stent protection, has nothing to do with this study.  It was the study that was used by the FDA to approve Plavix and then we used Plavix however we wanted.

What was the real risk of developing diabetes?  What was the characteristics of this group?  What was it about this 7% that made their doctors put them on  a statin in the first place?  Were they more likely to develop diabetes anyway?  Did their weight increase over the time of the study?  Was there any offsetting benefit by the use of statin?  None of these questions are answered only that “statins cause diabetes.”

Some more pertinent facts next.

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