Wednesday, December 31, 2008

Happy New Year / Anniversay and Best and Worst in Medicine 2008

I started this blog one year ago, and has been a phenomenal experience. I have enjoyed posting and reading your responses. I had no idea how much work a medical blog would be and have a great amount of respect for physicians like Kevin Pho of KevinMd and Robert Centor of DB's Medical Rants who also manage a heavy clinical load and are for more prolific then I have been. Though physician blogs range from sharing experiences to deliberating they health care system, my main purpose of this blog was to clarify medical issues that are discussed in the media. In today's New England Journal of Medicine, Susan Dentzer discusses some of the pitfalls of health care journalism. I am hopeful that this blog has helped filled some of these gaps. Here are some of the Best and Worst of 2008.

Vytorin is Out
The EHANCE trial which I discussed in Vytorin and Zetia: What to do now? failed to show any major benefit over generic simvastatin alone. The company tried their best (as I shared the letter the sent me in Dear Doctor: Vytorin ) the make excuses, but the reality is that they never proved the benefit of having two drugs to lower cholesterol when a higher dose of a statin could do the trick. Whether or not it is the LDL cholesterol or the drug used to lower it is still debateable, but for now, statins should be used to achieve cholesterol goals. However, if goals can not be acheived with a statin alone or statins can not be tolerated adding Zetia is not a bad option as showe in the SANDS trial (Zetia In, Vytorin Out)

Too Low Could Be Bad for Diabetics
The media got it wrong when the reported that the ACCORD study was stopped (ACCORD Study: Don't stop your diabetes medicines, Please! ) Both groups did much better than would have been expected, and some argue that the trial should not have been stopped. The message got out that lowering A1c might not be important, but it clearly is. However, their may be problems if you push the A1c too low.

Side Effects, Side Effects, Side Effects
Many of my posts (and the ones that got the most responses) regarding over-hyping side effects of drugs. The Wall Street Journal reported that Lipitor made women "stupid" (Lipitor and Memory Loss), Spiriva could cause stroke ( Spriva and Stroke: FDA warnings create buzz and confusion ), kids on Singulair might commit suicide ( Vytorin and Singulair: Problems for the Company, Confusion for the Public ) and of course concerns about the only new drug for the single leading preventable cause of death in the US in a decade ( Where's the Good News about Chantix? ) Some of this may be due to the fact that the FDA, under much public scrutiny, decided that it would report to the public drugs they were investigating, even if there was no clear evidence that these drugs were harmful ( More FDA warnings should not be cause for worry ). The bottom line is that there is no perfectly safe drug. Doctors and patients must balance the risk of medication side effects with the benefit it provides. If you are at high risk for a heart attack, it is probably worth risking a rare (though serious) side effect or Lipitor.

Cipro Causes Tendon Ruptures
That said.... there are some side effects, that even if uncommon deserve attention. In my post Tendon rupture with Cipro? FDA caves to Public Citizen, I question the FDA's decision to make a label change to Cipro, suggesting that they were merely responding to public pressure. I still contend that the announcement was not helpful to physicians because no real numbers were released, helping to determine a risk benefit ration. However, the many responses I got to this post suggest that there may be much more to this story. The difference between the Cipro example and Lipitor is that there are lots of other classes of antibiotics that can be used in most cases, whereas the best drugs to treat cholesterol are statins. In addition, the numbers for even the rare side effects of statins are well documented. Not so much for tendon ruptures with quinolones.

Prevention Magazine Creates a Scare
In probably the worst example of health care journalism, Men's Health Magazine published an article about 8 drugs doctors would never take (The truth on the 8 drugs doctors wouldn't take). I learned about this from a patient whose horrible asthma was finally well controlled on Advair, but stopped becuase her fiancee read that Advair could kill you. There were many problems with this article, but the worst was that they never actually asked physicians about the drugs they wouldn't take. I did (via Sermo) and most disagreed with the list (If you want to find out the 8 drugs doctors would never take....ask them!). PLEASE be careful of what you read, and talk to your doctor before stopping any medication.

Asthma Inhalers go Green
Asthma inhalers are no longer made with ozone depleting CFC's. This is good news, but some patients (and even physicians) were not aware of this and some of the implications, including direct costs to the patient. Hopefully, this post clarified some of the issues.

Salmeterol Issue Clarified
With so much negative (and often incorrect) information about asthma medications, specifically products containing long acting beta agonists (LABA's) such as Advair and Symbicort, it was great to post Good News for Asthma Patients which indicated that if LABA's were taking with an inhaled corticosteroid, they were safe. The FDA recently met on this (The Lowdown on LABA's) and seemed to agree. Now if only they will take away that boxed warning on Advair and Symbicort (Dear FDA, Remove the Boxed Warning from Advair and Symbicort )

Generics Just Fine
There is a lot of confusion about generics, but a study this year reported in JAMA showed that generics are generally just as good. With the high price of medications and our economy in the tank, most patients are switching to generics when they can. Hopefully they feel more comfortable doing this. (Generics Just As Good As Brand Name )

Students Not Going Into Primary Care
OK, this is obviously not good news, but I listed it under "best" for two reasons. First, I was one of the authors on the study showing that only 2% of US students are choosing to go into primary care internal medicine (Factors Associated with Medical Students' Career Choice Regarding Internal Medicine: Pay is Not Really One of Them!), and was proud to see the article published and discussed. More importantly, the article came at a critical time. The presidential debates had focused on covering the ininsured and decreasing the cost of health care. No one (except for thousands of bloggers) were really discussing the primary care crisis. I am hopeful that this study (and others that coincidentally came out at the same time) changed the discussion. We are now seeing the first time that the Obama administration has recognized the problems in primary care.

JUPITER: CRP Likely a Factor
OK, I am probably a little biased on this one too since we were one of the Jupiter sites ( Jupiter is Out, and the News is Good!). However, this study was important becaused it showed that there is more to the story than just LDL, since the patients in this study would not have normally qualified for statins. The anti-pharma and drug safety people will be critical of this study for a while (Remember when Sidney Wolfe wanted Crestor pulled from the market? Seems like Crestor has no more side effects then placebo, at least in this study). However, the data hear is pretty strong and I am checking CRP's on most adults.

Monday, December 22, 2008

CT Angiography, Dr. Nissen and Conflicts of Interest

For the record, I am not in favor of CT angiography, primarily due to the large doses of radiation. EBCT (Heartscans) have yet to be proven, but seem a much better technology. Last week the Wall Street Journal (via KevinMD) reported on a study in the Journal of the American College of Cardiology looking at the diagnositic accuracy of this test. Though the investigators (the lead author being a Netherland's radiologist) stated that CT angiography was " reliable for ruling out significant CAD in patients with stable and unstable anginal syndromes," what was reported in the media was Dr. Steve Nissen's comment and editorial that "in more than 50% of subjects, CT angiography ‘detected’ coronary obstructions that simply were not there.” Dr. Nissen's comments are not incorrect, and I do agree with his position on this one, but it should come as no surprise that a cardiologist (especially one's whose research primarily involves conventional angiography) comes out against CT angiography.

Conflicts of Interest
Conflicts of Interest in the medical field as reported in blogs and in the media usually concern the pharmaceutical industry. There are plenty of folks out there (Dr. Carlat and Center for Science in the Public Interest to name just a few) who bring attention to this. There is no question that a drug study sponsored by the drug's maker should be interpreted with caution. However, this doesn't mean that the data should be ignored. For example, when the Toyota car salesman tells you that the Prius is one of the most fuel efficient and reliable cars, he is certainly trying to get you to buy a Prius, but it doesn't mean his data is wrong or that you shouldn't buy the Prius. You just need to interpret his "data" with some caution. This concept does not just apply to the pharmaceutical industry, but other experts or groups of experts that make recommendations that may be biased based on other factors such as research, research interests, specialty, and even political motivation.

Conflicts in Guidelines
Guidelines are the best examples when conflicts of interest should be taken into account. The American Urologic Association currently recommends PSA testing for prostate cancer in men 50 and over. The U.S. Preventive Services Task Force not only states that "the current evidence is insufficient to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 years" but also recently recommended that prostate cancer NOT be screened for in men age 75 years or older. Both guidelines are written by medical experts, and both have looked at the same studies. The difference in interpretation has to do with potential biases. Urologists who see the horrors of prostate cancer on a regular basis, likely want to eliminate this disease, and additional have a financial incentive to detect prostate cancer (the more PSA tests, the more biopsies, the more surgeries). In contrast, the USPSTF is a government sponsored agency concerned not only with the health of Americans but also the cost. If PSA screening leads to more testing, biopsies and surgeries; then this will be more costly for the health care system (especially Medicare). Thus, neither interpretation of the same data is "right" or "wrong" but must be interpreted with attention to potential biases or motivations.

Other Conflicts
Research interests are another potential conflict. Someone who researches in a particular area is not likely to discredit what has made their career. Recently, I blogged about the JUPITER study which showed that CRP may be a very important marker for cardiovascular risk. It should be pointed out that Dr. Paul M Ridker, the lead author of the study, has made his career on CRP research and currently holds a patent on the test used in this study. Political motivation can also be a factor. In my comments on the fall out of the recent FDA panel's meeting on the safety of LABA's, I mentioned that Dr. David Graham had commented against these drugs (picked up by the NY times), but that he may have been politically motivated for making these statements since he was mostly wrong back in 2004 when warning congress of the "next Vioxx" and, as part of the safety arm of the FDA, alerting the public to safety issues might increase funding to his (agreeably) underfunded division in that agency. Which brings me back to Dr. Nissen.

Dr. Nissen's Potential Conflicts
Dr. Nissen is a cardiologist at the Cleveland Clinic, which recently announced that it would make its faculty's conflict of interest public. Interestingly,they report that Dr. Nissen has no conflicts, and though he does consult for a number of drug companies, he donated "all honoraria or consulting fees directly to non-profit organizations." First, no conflict is reported because the Cleveland Clinic does not consider research funding as a conflict of interest. In fact, Dr. Nissen, who has come out strong against Avandia, has had publications and research supported by Takeda, which makes Actos, Avandia's major competitor. In addition, the anti-pharma folks (correctly) suggest that any gift or relationship can pose a potential conflict. I do not criticize Dr. Nissen for his likely excellent consulting work, and would not do so even if he kept the money (since an expert should be paid for his time and expertise), but donating the money does not exempt him from any conflict. Finaly, and possibly most importantly, Dr. Nissen gained fame (which he deserves) for bringing attention to Vioxx, and helped get it removed from the market. Because of this attention (and the attention from Avandia) Dr. Nissen has been mentioned as one of the candidate to head up the FDA. Thus, until President Obama picks the person for the job, one should expect (as in the case of CT angiogram) that any comments from Dr. Nissen will likely reflect his desire to protect the public from unnecessary testing or the dangerous medicines from profit hungry drug companies.

My beef with Dr. Nissen is not that his research is funded by drug companies or that he feels donating honorarium exonerates him from conflicts of interest. Rather, as I have blogged many times (here, here here and here), his one poorly done study which scared the public and physicians about Avandia, has radically changed the way type 2 diabetes is being treated (and not for the good of patients in my opinion) and no one is calling him out on potential conflicts or motivations.

Saturday, December 20, 2008

Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III

It seems as if there are some individuals or groups of folks that just don't want new diabetes medicines. If diabetes was not a major problem in our country and/or if most patients with Type 2 diabetes were well controlled, then maybe this would not be so much of a problem. However, increasing rates of diabetes in the US have reached epidemic proportions, and most patients with Type 2 diabetes are not under good control (as defined by an A1c under 7%).

In the latest blow to Type 2 diabetics, the FDA recently announced that it will have stricter criteria before approving any new diabetes medications. Specifically, they are looking at cardiovascular risks:

We need to better understand the safety of new antidiabetic drugs. Therefore, companies should conduct a more thorough examination of their drugs' cardiovascular risks during the product's development stage," said Mary Parks, M.D., director, Division of Metabolism and Endocrinology Products, Center for
Drug Evaluation and Research (CDER), FDA

Though this may sound like a good thing, it means that it will take a lot more effort (time, money, patients needing to be enrolled in trials), for new diabetes pills to be approved. As the Wall Street Journal points out, this affects pending approval applications for one new diabetes drug called saxagliptin (made by Bristol-Myers Squibb Co. and AstraZeneca ) as well as a once weekly version of Byetta (made by Eli Lilly & Co. and Amylin Pharmaceuticals )

There is no question that there ought to be a balance between safety and efficacy when it comes to new drugs. Drugs that have substantial risks should be studied more carefully, even if that means delaying needed treatment for patients. The problem here is that the delayed approval for newer diabetes medicines which are currently needed is due to one highly publicized and poorly done meta-analysis, which has not be substantiated and in fact has been pretty much been disproven based on recent studies.

In the The Diabetes Conspiracy (Part I), I mentioned how the newer diabetes pills, specifically Advanida and Januvia, were being blamed for the increased cost of diabetes care, when in fact newer insulins were not only contributing equally but also being prescribed at a much faster pace. In Avandia Vindicated (Again): The Diabetes Conspiracy Part II , as well as other posts, I go over study after study which shows that there is no real heart attack risk seen with Avandia, since we now have randomized studies where over 26,000 patients have been studied for over 3.5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks or myocardial ischemia.

The FDA's decision to make it harder for newer diabetes drugs to be approved based on one poorly done, highly publicized and likely politically motivated study is the first action to likely have a real impact on patients. If older (and cheaper) drugs worked so well, then this wouldn't be a problem. However, the reality is that we need new drugs to get a handle on this very difficult to control disease. However, there are some that would like to turn back the clock, and only use older medications which we know aren't working. These folks are waving the banner of safety to defend their position. The next step, which will go beyond headlines and also have real patient impact will be the new diabetes guidelines, which will be published in just a few weeks. When these come out, I will comment on what I anticipate to be ridiculous and impractical recommendations in The Diabetes Conspiracy Part IV.

Friday, December 12, 2008

Dear FDA, Remove the Boxed Warning from Advair and Symbicort

If you heard the news, it seems I guessed right in my post on The Lowdown on LABA's . The FDA's advisers have recommended to withdraw the asthma indications for both LABA's, but reaffirmed the safety of ICS/LABA combinations such as Advair and Symbicort. However, all the media headlines make it sound like something bad has happened, and it is clear that some patients are already confused. Furthermore, given all the press that has surrounded this issue, the only way this will ever be put to rest is for the FDA to take the next step and remove the boxed warning on the ICS/LABA combination products.

Thus, here is a draft letter to the FDA that I will soon send to request such a move. Your comments are appreciated. Below the letter is the boxed warning for Symbicort for your reference.

Dear FDA,

I am thrilled that despite a very vocal minority that seems to wave the safety banner to promote their own agendas, your advisory panel has decided to remove the asthma indication for both formterol (Foradil) and salmeterol (Serevent), and feels strongly about the efficacy and safety of ICS/LABA combinations (Advair, Symbicort) for the treatment of asthma. The problem is that all of the news headlines which state "F.D.A. Panel Votes to Ban Asthma Drugs" and "FDA Advisers: Restrict Some Asthma Drugs" still continue to scare patients. I have one patient whose previously poorly controlled asthma was improved with Advair, but stopped because of an article she read in Men's Health Magazine that implied no doctor would ever prescribe this.

Almost all the controversy regarding LABA's has come from the SMART study, which showed a problem with salmeterol taken alone, but showed no issue when taken with an inhaled corticosteroid. At the time, you decided to give a boxed warning to all products containing LABA's. However in light of the pages and pages of data you reviwed before the recent committee meeting as well as your advisor's recommendations, it seems that now would be the time to reconsider this. The only way to definitely answer this question is a randomized trial of patients on ICS, with half on LABA and half on placebo or increased ICS does, looking at serious exacerbation or asthma death. The problem is that since these events are so rare, and since ICS/LABA does not seem to cause a problem, it would likely take a study of more than 200,000 patients to show what we already know; that ICS/LABA combination is safe and effective for asthma. In addition, no drug company or even the NIH would ever fund such a study.

Though asthma mortality has gone down since the mid-90's, despite an increasing prevalence (and probably helped with the introduction of LABA's), asthma morbidity continues to be a problem. Over 5000 ER visits and 11 deaths a day are due to asthma. ICS/LABA is the most effective treatment for asthma, but some patients and even physicians are concerned about taking them because of the LABA controversy caused primarily by the SMART study. The only way reassure doctors, patients, critics and the media that Advair and Symbicort are safe and effective is to remove the boxed warning from their labels. I truly hope you will consider this.


Dr. Matthew Mintz

Boxed Warning for Symbicort (Advair's is similar)

Important Safety InformationLong acting beta2-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low-to-medium dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol may apply to formoterol (a long-acting beta2-adrenergic agonist), one of the active ingredients in SYMBICORT.

Thursday, December 11, 2008

Asthma Medication: Calling Out the Safey Advocates

I posted "The Low Down on LABA's" precisely because I knew there would be a lot coming out in the media on this controversial topic. Of the media reports, the one most interesting to me is Advisory Panel Weighs Conflict on Asthma Drugs from yesterday's NY Times, which highlight what seems like a huge rift between the FDA Safety folks and the FDA's clinical folks. According to the NY Times:

Dr. David Graham, a safety official in the Food and Drug Administration, strongly recommended that the drugs, Advair, Symbicort, Serevent and Foradil, no longer be used to treat asthma in adults or children because they provide few benefits over simple steroid treatment and have serious risks. He said their use in children was particularly problematic.

Do you remember Dr. David Graham? He was the FDA insider who testified in front of Congress back in November 2004 right after the whole Vioxx fiasco. When asked what other drugs to be concerned about, he listed 5: Crestor, Meridia, Accutane, Bextra and Serevent. The head of the FDA immediately sent out a notice the following day stating the Dr. Graham's testimony did not represent that of the FDA, and that Dr. Graham was reporting his own opinion. Thus, Dr. Graham has for a long time been concerned with LABA's, and will likely continue to have strong statements against these medications (who likes to admit they were wrong?).

However, how did he do on the other 4? Well, he was right on Bextra which was pulled from the market in 2005. This is a drug similar to Vioxx, with similar cardiovascular problems. Interestingly, Celebrex (another similar drug) remains on the market and has not shown the same type of problems. Both Accutane and Merridia continue to remain on the market and in the past 4-5 years haven't shown the problems that Dr. Graham was concerned about. Finally, Crestor which folks like Sidney Wolfe wanted off the market was completely vindicated by the FDA in March of 2005, and recently I mentioned that one of the things missed in the media about the Jupiter trial was that in almost 18,000 patients taking Crestor 20mg or placebo there was no difference in side effects. Thus, excluding LABA's, Dr. Graham was only on target about the cousin of Vioxx that Dr. Steve Nissen showed was unsafe.

(Though I have no actual knowledge of this, I suspect it was Graham that tipped off Nissen on the FDA's data on Avandia. I have mentioned countless times (here here and here) about how this one highly publicized, poorly done meta-analysis has caused hysteria about safety issues with this medication that just doesn't seem to hold up with recent data).

Drug safety is incredibly important. As a physician I take an oath not to harm my patients. However, be very cautious in interpreting comments from folks like Drs. Nissen, Wolfe and Graham who also seem to be concerned with safety, but also like to get their name in the papers and push their own agendas. It has been reported that Dr. Nissen is on the list of folks being considered to head up the FDA. Could this explain why he made so much noise about Avandia?

Sunday, December 7, 2008

The Lowdown on LABA's

There has been some recent media coverage ( NY times, AP) on the safety of LABA's (long acting beta 2 agonists) which are used to treat both asthma and COPD. This stems from a recent release of data from the FDA (here is the 6.5MB 460 page document-download if you dare) in preparation for and advisory committee this Tuesday and Wednesday regarding the safety of LABA's. The meta-analysis released on 12/5 generated some additional safety concerns. GSK and Astra Zeneca (makers of Advair and Symbicort respectively, products that both contain LABA's) have already issued press releases. The results of the advisory committee meeting this week could range from pulling all LABA products from the market to keeping the on the market with even less cautionary warnings due to safety reassurances.

To prepare you for what is likely to be a major showdown this week between Big Pharma, the FDA, clinicians, consumer rights activitists and patient advocates on this critically important and controversial topic, I am providing you with the "Lowdown on LABA's."

The Role of LABA's
Inhaled corticosteroids (ICS) have been one of most significant advances in the treatment of asthma. Prior to this, asthmatics used short acting beta 2 agonists (SABA's) to relieve their symptoms, but this did not treat the underlying disease caused by inflammation. ICS's are anti-inflammatory and have been shown to improve symptoms, reduce the need for hospitalization and even save lives. For this reason the 2007 NIH asthma guidelines recommends ICS as first line therapy for all asthmatics. However, sometime ICS are not enough. LABA's were introduced in the late 90's and had substantial impact. Unlike SABA's which last only a few hours and are intended to take as needed, LABA's last 12 hours and were intended to be taken on a regular basis. Interestingly, though LABA's are indicated for the treatment of asthma, the NIH and WHO guidelines never intended LABA's to be used without an ICS, but rather used in combination. It should be no surprise that Advair, a combination of ICS plus LABA, became one of the world's most popular prescription drugs and the number one maintanence inhaler for asthma. Since other asthma drugs existed (theophyline, chromolyn sodium) or were recent to the market (Singulair), there was some question in the late 90's as to which was the next medication to add after ICS. In 2002, the NIH answered this question, stating that after ICS, adding a LABA was the next best choice. It was better than doubling the dose of ICS, better than adding Singulair, etc. The NIH stated that the evidence was clear: if ICS alone doesn't work, add a LABA.

The SMART study
I have blogged about the SMART study several times. In response to The truth on the 8 drugs doctors wouldn't take and regarding Good News for Asthma Patients. Basically, due to possible safety concerns due to salmeterol (LABA used in Advair), GSK conducted a very large (over 23,00 patients) study safety study. The problem was that it didn't study only asthmatics taking ICS, but asthmatics taking any medication. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including death. Though there have been criticisms of the study, the FDA applied a boxed warning not only to salmeterol, but all LABAs and products containing LABAs. In the analysis it was clear that most of the problems came from taking LABA's alone, and that there was no increased problem (regardless of ethnicity) when using a LABA with and ICS (no one taking Advair or Symbicort equivalents in the study died). However, this was not enough for the FDA or critics to give ICS plus LABA products a pass on the boxed warning. Several other papers came out regarding this. Salpeter's meta-analysis received a lot of attention (cited in the popluar men's health article and had Katie Couric repeating that "4 of 5 asthma deaths were due to Advair). However, the meta-analysis was flawed because all of the death data was based on the SMART study, and like the SMART study some patients were taking ICS and some were not. In addition, if anything, since the introduction of LABA's the asthma death rate has gone down, not up, suggesting that LABA's may be one of the reasons asthma death has decreased to an all time low. A recent meta-analysis showed that when LABA's are used (as they always should have been) with an ICS, there were no increased exacerbations and deaths, and as in the previous studies, patients did better. Regardless, SMART could not be put to rest and the 2007 NIH guidelines backed down from the 2002 preference of ICS +LABA, suggesting doctors weigh the risks and benefits of ICS + LABA vs. increasing the ICS dose. In addition, the FDA decided it would revisit the issue, and thus the meeting this week is now being held.

The FDA Data
The agenda and other material can be found here, here and here. Several of the advisory committees basically plan to review all of the data and make recommendations to the FDA for a final decision.

In preparation for this big meeting, the FDA did it's own meta-analysis of 110 trials of two LABA's -formoterol (Foradil) and salmeterol (Serevent)- and the two ICS/LABA combinations - salmeterol/fluticasone (Advair), and formoterol/budesonide (Symbicort)-available in the US; however, most of the data come from salmeterol (Severent/Advair) studies. They looked at over 60,000 patients, of which the SMART study accounted for over 40%. They found an increased risk of hospitalization and asthma related death for patients on LABA's, particularly in children ages 4 to 11, with a risk difference estimate of 14.83 per 1,000 participants (95% CI, 3.24, 26.45). There were 20 asthma-related deaths in the 110 studies, and 16 of those occurred among patients taking long-acting beta agonists. However, 16 of these deaths occured in SMART and while 13 deaths occured on salmeterol and 3 on the placebo; patients on ICS showed no difference in asthma related deaths (4 vs. 3).
In fact, review of much of the FDA's and the drug company's various studies seem to further add weight to the fact that 1) when used alone, LABA's can cause bad outcomes and even death and 2) when used in combination with ICS, they seem to be the most effective as well as safe option (like the NIH's 2002 recommendation).

What will happen?
This is quite hard to predict since even if the advisory committee makes a recommendation, the FDA may not necessarily follow it. The other confounding variable is that where no guideline ever recommended that LABA's be taken alone in an asthmatic, for COPD, LABA's (used BEFORE adding and ICS) remain one of the cornerstones of therapy. Thus, LABA's couldn't get removed from the market completely since their use is still deemed essential for COPD.

In my opinion, the best case scenario is that the FDA will finally but the SMART study into context: discourage the use of LABA's without an ICS by changing the boxed warning on formoterol (Foradil) and salmeterol (Serevent) to state that they should NOT be used in asthma and only used in COPD, as well as reassure patients and clinicians of the safety of LABA's plus and ICS by removing the boxed warnings from salmeterol/fluticasone (Advair), and formoterol/budesonide (Symbicort). Since there is so much political pressure on the FDA to protect the public, my guess is that the former will likely occur but the later will likely not. I do remain hopeful that the FDA will consider modified boxed warning on Advair and Symbicort to reflect the newly analized data and reassure the public, patients and physicians regarding the safety of ICS + LABA.

Bottom Line
Asthma remains a disease that causes substantial morbidity and mortality. Each day in the US there are 1300 hospitalizations, 5000 ER visits and 11 deaths due to asthma. Regardless of the outcome of the FDA advisory meeting, the FDA's recommendation or what you may hear in the media; the use of inhaled corticosteroids plus a long acting bronchodilator is one the most effective, as well as safe, options for adults and children whose asthma can not be controlled with a low dose inhaled steroid alone.

Tuesday, December 2, 2008

Generics Just As Good As Brand Name

MSNBC has picked up on a study that has otherwise not generated a great deal of media attention, but that I think is rather important. The study, published in today's issue of JAMA was systematic review (look for all possible studies) and meta-analysis (analyzes data from multiple studies) that compared generic to brand name medications for common heart conditions such as high blood pressure and high cholesterol. They essentially found no difference in both the efficacy and safety of generic medicines compared to the same brand name medications.

This study is very important because there still exists a common misconception that generics are just not as good as the real thing. This misconception is held by both physicians and patients. In fact, in their analysis, the authors of the JAMA study looked at the conclusions of the individual studies which similarly suggest (despite the data showing otherwise) that generics might not be a great substitute. The authors suggest that one possible reason could be potential conflicts of interest from the individual investigators, and about half the studies analyzed did not disclose any conflicts of interest.

As health care cost continue to rise and the economy seems to get worse by the day, patients are becoming more used to taking generic medications, especially when many are available at Walmart for $4. However, the belief that generics do not work as well likely still persists. As I mentioned in an earlier post regarding the nocebo effect, if a patient doesn't think a medications is going to work, there is at least a 30% chance that it won't. In addition, patients who value their health care and believe generics to be inferior, may needlessly waste their out of pocket health care dollars paying expensive co-pays.

When a new medication is approved by the FDA, the drug company must prove that it is both safe and effective. When the drug company loses exclusivity on their patent, generic manufactures can duplicate the drug. Unlike the original brand drug, all the generic manufacturer has to prove to the FDA is that the blood levels of the drug are virtually equivalent to the original branded product, which is much easier to do. This is why generics are so cheap: the generic companies have virtually no investment in research, and they have very little in expenses to get their drug approved by the FDA (and they also don't spend a lot of money on marketing to physicians).

This study confirms that there is really no difference between generic pills and branded pills when it comes to safety and efficacy. Since the pills are not exactly the same, rarely patients might have an adverse event when switching such as an allergic reaction to a dye in the pill. However, this is very rare. The only time a difference really matters is when a pill has a narrow therapeutic window, which means a tiny change in dose can have a big effect. Common drugs with narrow therapeutic windows are hormones (like thyroid replacement medications), blood thinners (coumadin/warfarin), and pills whose levels need to be monitored (like tegretol). However, in the JAMA study even warfarin/coumadin performed similarly. Thus, even these switches are safe, though more careful monitoring is needed.

This does not necessarily mean that you should always use generics. Some branded products which are not yet available in generic form, are often needed to achieve the desired effect where a generic would likely fail. A good example is cholesterol lowering medications. The generic statins, simvistatin in particular, will get you close to a 40% reduction in bad cholesterol at the maxium dose, but for those patients who need much greater lowering of their cholesterol, drugs like Lipitor (which goes generic in 2011) or Crestor will be needed.

Bottom Line: If a generic will do the trick for your particular disease, then you should take the generic confidently. Though the study did not specifically address this, the same principle applies to over the counter medications. Doesn't make sense to spend $8.99 on extra strength Tylenol, when you can get the CVS brand for $6.99.

Monday, December 1, 2008

The Cost of Health Care

Today I received a message from a patient who needed early refills of two of his regular medicines: medicines that he takes every day and has taken for years. This patient was going out of the country and needed to get his refills earlier than scheduled so he could have a full supply with him, otherwise he would run out of medications overseas. The call (taken by my staff) was a request for me to call his insurance company to request an override for an early refill. He had attempted to refill these meds ahead of schedule, but the pharmacy told him his insurance company would not pay without an override.

Much has been said/written/blogged about the cost of health care. A malpractice environment that leads to unnecessary testing, a system where the more you do the more you get paid, and the uninsured all some of the popular ones. However, recently there has been little discussion of the cost of administrative overhead.

Referrals, prior authorizations, overrides, etc. are all tools designed to deny patients care. They have been particularly useful for for-profit insurance companies who spend much more on administrative costs then government health insurances (Medicare, the VA) but don't provide better quality. The for-profits spend money on these services because health care is so expensive that the only way to make a profit is to deny patients care.

However, these administrative costs are for the insurers. What about the administrative costs to the physician? For my patient today who needed an early refill, no intervention was really needed by staff or a physician. The pharmacist should have been able to refill the medication early based upon their records. However, my staff had to spend the time to take the call and record the message. I will now have to spend the time to call the insurance company for the override. All this extra time not only takes away time from care for patients who really need it, but also increases costs. Since I am spending time doing things like prior-authorizations and referrals and not generating income from these activities (though incurring liability), I must compensate, usually by seeing more patients in a shorter amount of time. Since insurance hassles take a tremendous amount of staff time, I need to hire more staff.

Our institution is one of the largest multi-speciality practices in D.C. Our Division of Internal Medicine has about 25 providers (not all full time). We have hired four full time staff members that do nothing all day but fill out referral forms for patients so they can see the specialists that we think our patients should see. Their salaries are not paid by the insurance companies who necessitate their work, so they come from the small payments we receive from the insurance companies.

The for-profits have quickly learned that one way to decrease health care costs (and thus profit) is to deny care to patients using these methods. The extra work on the physician and their staff is not covered. As we expand health care and think about ways to cut costs, surely similar methods will be used. Any new health care system (i.e. the medical home) must not just increase payments to primary care physicians for the hard medical work they already do, but also reduce administrative burden and/or cover the expense of such burdens.