Archive for July, 2010
Gimmee a Pill Part Deux
Is obesity a disease or a condition? If it is a disease, is it chronic or situational? Does obesity raise itself to a problem which requires the might of pharmaceutical research to overcome, or is it a societal problem? What do you do when one third of the United States population is obese? These are some of the questions that the FDA and its committees have been wrestling with lately.
The weight loss industry is a multi billion dollar a year business and as anyone who has read the labels at the health food stores knows, these substances sold as pills are not FDA approved. Their efficacy is also not known or tested, but that doesn’t really matter because if Kim Kardashian said it works, it’s good enough for me. Most of these diet aides contain substances that allegedly increase metabolism like caffeine or guarana which contains twice the amount of caffeine that coffee beans do to provide “the burn”.
At the present time “real” drugs to make people lose weight come in two basic categories. Fat blockers, like the drug orlistat known as Alli and produced by GlaxoSmithKline, is one type. This drug is the equivalent of a movie which goes straight to DVD. This drug went almost straight to over the counter because although it works, it is punitive. The drug works by blocking the absorption of fat in what we eat. It causes a condition much like those individuals who lack pancreatic enzymes and cannot digest food properly. The outcome, if you foul up and eat something you should not, is pretty unpleasant. Be sure to buy extra underwear!
The second class of drugs target serotonin. This was one part of the famous Fen-Phen combo that was pulled by the FDA after reports of valvular pathology appeared far removed from the time frame of study. To make it clear - if a study lasts one year, how do we know what will happen if five years later you are still taking the drug? After taking the drug for many years, some patients developed what clearly was a side effect related to fenfluramine. So many law suits were filed that the company went bankrupt.
Two new drugs have appeared on the horizon, but strike me as lacking what’s needed. The first is a compound called Qnexa which is a combination of phentermine (how original) and topiramate which is an approved drug for seizure prevention and migraine prevention. I do not understand the mechanism of the action, but it appears that this combination allows patients to lose weight. However, it also causes the side effects of and I quote “depression, anxiety, sleep disorders, attention deficit disorders, memory difficulty, language difficulty, increased heart rate and teratogenicity (deformed babies)” to name a few. As Doctor Evil would say “Riiiiiight”.
This drug was not approved at the FDA committee meeting. It is unlikely that it will ever pass the hurdles. Stay tuned for the second drug.
Gimmee a Pill!
When I was a child I had four great-grandparents. Two were from Russia and two were from Poland. My grandparents were actually born in the United States. My last great-grandparent died at the age of 96 when I was 31 and in training after medical school. She was someone I knew as a full person and not just as a grandparent. Interestingly enough she actually came to the United States not once but twice. She returned to Russia because she did not like the conditions in New York City when my maternal grandmother was five years old. She quickly returned to the United States when she got back to Russia.
My great grandmother suffered from congestive heart failure and loved to eat anything salty. Pickles, lox you name it she ate it and then she would call me up and complain she was short of breath. She wanted no part of diet restriction and all she would say was “Gimmee a pill”. Then she would infer that I wasn’t as smart as I should have been because I didn’t have a pill to solve her problem.
We as a population have become much like my great grandmother. Maybe she was on to something. The area of life which comes to mind the fastest is that of weight loss. No one wants to hear or deal with the knowledge base we have. Eat less, actually a great deal less, and get some exercise, actually a great deal of exercise, and guess what? You will lose weight and keep it off. Whoa that’s just not going to cut it. “Gimmee a pill” screams America and what America wants is big Pharma to continue to serve up.
What is a significant weight loss induced by pills? Give up? One would hope it would be 20-30 pounds, or in the case of gastric bypass or the Biggest Loser TV show, at least an entire person worth. You will find out that’s not the case.
Should drugs even be used in what is generally a self induced problem? Obesity is epidemic in this country, and childhood obesity has become a national disaster that will dwarf all health care spending deficits. As you will see in my next blog, approving these drugs is not an easy task, and as most people will remember the diet drug combo known as Phen-Fen was removed from the market only when its serious side effect of heart valve problems became an issue. This has made it even harder to approve these drugs as the heart problems did not become evident for many years after the drugs were marketed. What is “reasonably safe” and is this a problem for which there is a “medical solution”?
I will discuss these issues in my next blog. Until then I’m going for ice cream.
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.
How to Proceed?
If you fall into the age groups that I discussed in my last blog, what should you do? First, remember that this discussion is only about asymptomatic patients. Those that do not have a history of heart attack, stroke or do not suffer from claudication, which is pain in the legs on exertion.
First and foremost, if you are smoking stop, and after you stop, stay stopped. Believe me it is not so simple if you judge from what my patients tell me. Cholesterol levels are not the whole answer. There is no such thing as a normal cholesterol level. Each patient’s level is a number and then an atherogenicity potential. Although these can be determined by particle testing and such, our knowledge remains incomplete and our methods crude.
What has been proposed is finding a simple and reliable method to identify which patients have evidence of atherosclerotic changes in their vessels and then try to prevent the furtherance of the disease process by medical i.e. lipid lowering treatment. We have these methods available to us now and the article cited in my previous blog provides the background for these methods. One is calcium scoring by electron beam imaging.
It is fast, simple and accurate. However, it provides individuals with a small dose of radiation (median 2.3 mSv). If negative, it virtually excludes significant atherosclerosis and the chance of a cardiovascular event in 5-10 years is .6% at the greatest.
Another modality is carotid ultrasound which is done slightly differently than normal and looks at the intima- media and measures the thickness of it. This measurement has been shown to correlate with the disease process. It is not as predictive as calcium scoring but does not use radiation. It is not clear whether both tests are additive.
Imaging in this manner and using the SHAPE guidelines, it is estimated that almost 50% of the patients screened would be in a higher class and eligible for lipid lowering therapy. The cost of this screening varies, but some institutions offer it at around $150.
All of the information we have to date supports screening for all patients who have intermediate risk based on Framingham Risk Scores in addition to those patients with low HDLs. It is very unlikely that a large randomized study will ever be done. Who wants to be in the placebo group? We just have to manage with common sense.
Is it true that lipid lowering therapy saves lives? In my next blog I will explore that.
Can We Do Better?
A considerable number of strategies in American medicine are troubling. One of the most troubling is our insistence on spending large amounts of resources treating illnesses that might be able to be prevented at an earlier stage. Simple examples are providing better treatment of diabetes and hypertension by making the drugs and materials needed more readily available to patients.
As the readers of my blogs know, a large proportion of this country’s resources go to treating coronary artery disease and its consequences. Couldn’t we do better if we prevented this? Roughly 50% of the major cardiovascular events that occur in this country every year, which by the way amounts to over 700,000, occur without warning. At the time of writing in 2006, it was felt that by implementing the SHAPE recommendations 21.5 billion dollars could be saved.
This subject has been discussed before. In 2006 a taskforce was developed to address this problem and provided the SHAPE guidelines. SHAPE stands for Screening for Heart Attack Prevention and Education. It was a committee set up by big Pharma mostly Pfizer and never received much support mostly because it would make heavy use of drugs i.e. Lipitor, made by Pfizer, in its prevention mode.
This past week one of the editorial leaders of the SHAPE study Dr. Prediman Shah was the lead author on an article published in the Journal of the American College of Cardiology titled Screening Asymptomatic Subjects for Subclinical Atherosclerosis . I want to point out that Dr. Shah, who practices at Cedars Sinai in Los Angeles, is a widely published and respected researcher.
Screening for disease, although it sounds like a perfect solution, is sometimes no solution at all. One can point to the use of the PSA test for prostate disease. Screening with it has not led to changes in the diagnosis of advanced prostate disease or lowered the death rate of prostate cancer. Recently, the physician who invented the test wrote that he thought our use of it should be reevaluated.
SHAPE recommended that all asymptomatic men 45-75 years old and all women 55-75 years old be screened. There are two main ways this is done. The first is the Framingham Risk Score that I have blogged about in the past. This score which identifies the risk of events in ten and twenty year periods has been found to be useful. It is highly dependent on blood pressure and cholesterol values as those were the only modalities available at the time. If you go to the online calculator fiddle with the numbers so you can see the changes in risk that occur. Guess what? This approach has never been subjected to a randomized clinical trial and at this point never will be because it is not ethical.
Next…what about imaging?
New Tools for Atrial Fibrillation
I have blogged about atrial fibrillation many times as it is a constant feature in the practice of cardiology. An estimated 2.2 million patients in the United States alone have this problem. It has been difficult to prove in some patients and very difficult to follow. The facts are extraordinary.
If you have atrial fibrillation and go out of it by any means, the likelihood is that at one point in time, you will be back in it. If a physician places you on a drug, there is only a 50% chance that it will keep you in normal rhythm. If you have a procedure to terminate it, the range of one year success is variable from 50%-70%. We do not even have a way to figure out what your rhythm or rate control success is on a long term basis.
Until now — Medtronic, a major device company–has released a novel device. A study associated with the device has been published in Circ Arrhythm Electrophysiol. 2010; 3:141-147. This study documents the usefulness of this unique device.
The device records and stores data obtained from the heart without the need for leads into the heart such as a pacemaker would have. It is implanted in a simple procedure under your skin near your heart and is able to sense the electrical activity of your heart without wires into your heart. The procedure takes roughly ten minutes to place the device, and about the same amount of time to remove it. This can be done in an outpatient setting. The device will last up to three years so it provides a long term view of a patient’s atrial fibrillation and whether drug or ablation therapy is working for the patient.
This device also allows the diagnosis of patients who have intermittent symptoms that are virtually impossible to figure out using 24 hour holter monitors. The sensitivity of the device for atrial fibrillation was 96% and it was correct in identifying the problem 85% of the time. This device will also “download” its information wirelessly from a remote location so patients can send reports without going to the doctor’s office and patients can send reports if they sense something that troubles them.
Devices such as this will lead to a new paradigm of treatment for atrial fibrillation, as we can now have long term data which was unable to be obtained previously. This will lead to better treatments and to a better understanding of the disease process. If you cannot study it you can’t make progress, and we now have a tool to help.
New Toys for the Electricians
Electrophysiology is the subspecialty of cardiology that deals with the electrical problems of the heart. At times the heart develops rhythms that break down into the fast rhythms, the slow rhythms and the lethal rhythms. I have blogged in the past about the development of ICDs or implantable defibrillators and now we are seeing the next generation of these devices.
This paper was published online at the NEJM website and presented at the Heart Rhythm Society Meeting in May. It was presented by Dr. Bardy who is the founder of the company as well as one of the inventers of the device. Dr. Bardy works at the Cleveland Clinic in Cleveland Ohio.
A conventional ICD is implanted by placing a wire into the right top chamber of the heart known as the atrium and a “shocking catheter” into the right lower chamber of the heart known as the ventricle. There are other ways to do this but the descriptions are outside the scope of this blog. To do this, the wires are in contact with the blood of the body and special equipment and x-ray is need. This new device uses a generator that is implanted in the top part of the chest underneath the skin as in a standard ICD. The new part is an array shocking catheter which is placed under the skin near the heart alongside the sternum. It is not in actual contact with the heart and is not in the blood stream.
The procedure requires no x-ray and can be done in any suitable surgical location. This device requires much more energy to work, almost twice as much, and the device is capable of delivering an astounding 80 joules of energy. Most ICDs deliver shocks in the range of 18 joules.
The study encompassed 55 patients followed for a short 10 months. One hundren and thirty seven bouts of induced rhythm were terminated. Twelve episodes of spontaneous rhythms were successfully treated by the device. For one patient the device would not successfully work in the lab and the patient received a standard ICD. One patient died of renal failure unrelated to the study.
This is an exciting advance but not ready for prime time. The device lacks many of the standard features of ICDs; perhaps the most important one is that of tiered therapy. What is meant by that is that the device delivers therapy in many ways and often terminates the rhythm without delivering a full shock. In addition the ICDs often function as backup pacemakers for patients.
Not quite ready, but an exciting advance and I applaud the thought leaders here.
Next: A new device for atrial fibrillation…
A win for a new drug
It’s not often that drug studies are stopped early because of success. Usually they are stopped early because of either a structural problem in the protocol or for reasons of safety. Lately, studies stop because the companies have gone bankrupt.
Apixaban is a drug that we are studying and our study continues in follow-up. A sister study done was stopped because the drug proved significantly more beneficial and it was no longer ethical to proceed.
This drug is one of several in development of a new class of drugs. These compounds are known as factor xa inhibitors. They block the clotting cascade at a different point than Coumadin and are going “head to head” against Coumadin in many studies. One is close to approval in the US and is being presented to the FDA for final approval next month.
The use of these drugs will be felt most in the treatment of atrial fibrillation. As I have blogged about many times, atrial fibrillation is increasing in prevalence as our population grows older and about 10% of people over the age of 80 are affected by it. The big problem with atrial fibrillation is the strokes that occur. If no anticoagulation is given, the risk of stroke is 5% a year. If patients take Coumadin the risk is cut to 1%. It is not perfect. Coumadin however becomes more and more difficult to take as patients get older and comes with many restrictions. These new drugs do not as yet have important drug interactions (I can assure you there will be some) and have no dietary interactions like Coumadin does. The one drawback of the drug is that it must be taken twice a day.
The study reported concerned those patients that can’t or won’t take Coumadin. 5,600 patients received either 5 mg of apixaban or aspirin in varying doses. The study was stopped because, again, aspirin proved not effective in preventing strokes. I should mention that Plavix and the combination of Plavix and aspirin have never been found to be effective either.
So, it will likely be that this drug will be an option for patients who will receive the benefit and sustain fewer side effects than taking Coumadin. This is real progress and this drug is eagerly being awaited by both physicians and patients. It will be a “blockbuster” drug for the company who gets approval first. By the way, a “blockbuster drug” is one that brings in over a billion dollars a year.
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