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.

Wednesday, November 26, 2008

More on Fluoroquinolone Related Tendon Injuries

The Medical Letter is an excellent source for information about medications. It is independent and thus not funded by the pharmaceutical industry. In addition, it appears to have no political agenda or bias, such as the FDA for example that might err on the side of caution and/or informing the public based on recent scrutiny or Public Citizen's Best Pills Worst Pills which is pretty blatantly anti-industry. It is the closest thing to a Consumer Reports for drugs that we have. It is a subsription based service, so you will have to pay if you want to read their evaluations.

However, I (hopefully legally) copied some of their statements on the issue of fluoroquinolone-related tendon injury because my post on Tendon rupture with Cipro? FDA caves to Public Citizen has been the my blog's most responded to and "hit" post. I initially complained that the FDA was adding a boxed warning without giving physicians any real data on actually risks. In my opinion it seemed to caving in to public and political pressure. However, the vast number of responses I received seem to indicate their may actually be more to the story. I would be nice if the FDA would release all the data behind their boxed warnining. However, The Medical Letter has done their own research and commented.

Fluoroquinolone-related tendon injury is rare; estimates for its incidence in
the general population range from 0.14% to 0.4%. The risk is higher for patients
>60 years old and for those taking corticosteroids. For patients with organ
transplants, the incidence may be as high as 15%. A case-control study in Italy
involving 22,194 cases of non-traumatic tendinitis and 104,906 controls found
that fluoroquinolone use was significantly associated with tendon disorders in
general (OR 1.7; 95% CI 1.4-2.0), tendon rupture (OR 1.3; 95% CI 1.0-1.8), and
Achilles tendon rupture (OR 4.1; 95% CI 1.8-9.6). Achilles tendon rupture
occurred with fluoroquinolone treatment in one of every 5989 patients in general
and in one of every 1638 patients >60 years old. Widespread use of
fluoroquinolones, particularly for treatment of respiratory infections, has
produced substantial bacterial resistance to this class of drugs and
has been
associated with an increase in the incidence and severity of Clostridium
difficile disease. Even when bacterial pneumonia is considered a likely
possibility, other drugs are generally preferred, at least in non-elderly,
otherwise healthy patients.

This kind of information is much more helpful then either FDA's boxed warning or Public Citizen's rant, mainly because it uses several sources of data. Fluorquinolones can be useful drugs, but based on all the current information, they really should only be used if equal or better options do not exist, especially for elderly patients.

Tuesday, November 18, 2008

When Drug Labels Make You Sick

An absolutely fabulous piece in (of all places) the Wall Street Journal called When Drug Labels Make You Sick . It asks the important question, "Is it a good idea to read about all the possible side effects of medications you're taking?"

The answer is definitely "no." The WSJ piece talks not only about the placebo effect (where taking a sugar pill makes you better), but also about the nocebo effect which is essentially thinking a pill you are taking will make you sick, actually will make you sick. Both are powerful forces. The reason we do randomized placebo controlled trials is because in virtually every study, patients taking a placebo get better, by about 25%. The same is also true of side effects of studies, i.e. patients enrolled in studies who don't know whether or not they are getting a real medicine are likely to report side effects. These side effects are ones that people commonly have such as headache, nausea, anxiety, etc.

What the Wall Street Journal does not delve into is how medication side effects are reported. This is critical in understanding both why you shouldn't read all the side effects, as well as which side effects you should actually pay attention to.

Let's use the example of Crestor. I choose this medication, because of the recently published, and highly controversial Jupiter study which I blogged about recently used Crestor 20mg a day.

If you go to Crestor's web site, you first see bulleted side effects of Headache, Muscle pain , Abdominal pain, Weakness and Nausea. Next it says "For a complete list, see the full Prescribing Information for CRESTOR," which is a link to the package insert (more on that in a minute). Finally, it states "If you develop any unexplained muscle pain, tenderness, or weakness at any time during treatment with CRESTOR (especially if you also have a fever or feel ill), call your doctor right away, as these symptoms could be a sign of a rare but serious side effect." If that last part sounds like a TV ad, it's because it is the identical language you see in the their TV commercial.

The package insert is the folded up piece of paper that comes with every prescription. It is designed to tell physicians everything they need to know about the drug: how it works, how well it works, precautions to be taken in prescribing such as interactions with other medications, and of course side effects. The FDA recently changed the format of the PI (as it is known in the industry) with the first page being a summary page. It lists all the major information up front. If you go to the PI, you will note that under "Adverse Reactions" are listed "headache, myalgia, abdominal pain, asthenia, and nausea" which are the same as "Headache, Muscle pain , Abdominal pain, Weakness and Nausea" from the web site. Just above, under Warnigns and Precautions list the severe muscle effects and liver enzyme monitoring. This is the stuff at the end of the TV commercials that the FDA mandates must be disclosed. Thus, if you go to the PI of Viagra, you will find the "erections lasting more than 4 hours" under Warnings and Precautions.

Here's the important thing to know: Side effects or Adverse Effects in the PI are reported effects that happened in 2% or more of the patients REGARDLESS OF WHETHER OR NOT IT WAS MORE THAN THOSE TAKING PLACEBO. If you look at Table 1 in the Crestor PI, you can see that the five side effects listed for Crestor occured at about the same rate for those taking Crestor as those taking placebo. 5.5% of Crestor patients had headache and 5.0% of placebo patients had a headache. Thus, headache is listed as a side effect, but does Crestor really cause headaches? Probably not. This is the nocebo effect that the WSJ piece was talking about. Headache is common, thus you would expect that in a study looking at a new pill, patients would likey report having headache regardless. However, both in what you receive from the pharmacy, what you Ads you see in magazines, and of course those TV commercials, the FDA requires the drug companies to list these as "side effects." The only true side effect caused by Crestor is likely muscle pain, which PI reveals to be 2.8% in Crestor, vs. 1.3% in placebo. In fact, muscle pain is about 3-5% in all statins (Lipitor, Zocor), is usually mild, and usually goes away. What was really interesting about the Jupiter study, which didn't really get picked up in the press, was that there was really no statistically significant difference in side effects of the close to 20,000 patients taking either Crestor 20mg or placebo.

Now the myalgia or rhabdomyolysis is a different story, which is why it is listed under Warnings and Precautions, and why the FDA mandates the be clearly stated. These effects can be very serious, and can even cause death. Fortunately, the occurrence is rare. The true rate of rhabdomyolysis is between 1/100,000 to greater than 1/1,000,000. As carefully documented by the FDA in their response to Dr. Sidney Wolfe who wanted Crestor pulled from the market, stated that rhabdo was rare, and was no different for Crestor than any other statin.

Bottom Line: The WSJ does a great job discussing both the placebo effect and nocebo effect. If you think a medication is going to work, it increases the chances that it will. If you think it is going to cause side effects, you also increase those chances. "Side effects" reported by the drug company are really anything that happened to 2% or more of the patients, regardless whether or not it was different than placebo. When asking about side effects, find out about true side effects (those that occurred much more often then in those taking placebo pills) as well as rare but potentially serious side effects. You will then need to weigh whether or not a small chance of having one of these rare but serious side effects is outweigh by the potential benefits of the drug. Statins decrease heart attacks and strokes, and deaths caused by either. Cardiovascular disease is the single leading cause of death in the US. Compared to a lottery like chance that you could have something seriously go wrong, you can see why these medications are the most commonly prescribed in the country.

Monday, November 17, 2008

Your Medicines Are Killing You

MSNBC just posted a piece called "Is Your Parent Over-Medicated?" This is one of many articles in the media designed to have us think that the medicines our physicians prescribe are, in general, harmful and more likely to hurt us then help us. I have blogged about this before ( The truth on the 8 drugs doctors wouldn't take). This piece, which discusses the author's concerns that her mom's memory problems were related to taking too many medications, is actually a re-print from Prevention Magazine.

There is no question that polypharmcy, or taking a whole lot of medicines, can be a major problem and is likely an issue for many Americans. This can be specifically a problem for elderly patients who metabolize medications differently, are more susceptible to side effects, and are more likely to see multiple physicians prescribing different medications.

However, a few critical points about a journalistic piece designed to have you consider stopping all of your medicines at once!. First, Neel, the pharmacist the author consulted with who no other name is given (not clear if Neel is the first or last name, or he such a famous pharmacist that he goes by only one name like Madonna or Cher) and only described as the "Georgia consultant pharmacist" is actually Armon Neel, Jr., PharmD, CGP, FASCP who has started a business of consultant pharmacists called Medication Xpert. Dr. Neel is certainly highly qualified. After looking at several of his detailed sample consultations on the web site, it seems like many of the recommendations of stopping medications are replaced by either stronger recommendations for diet and exercise and/or substitutions with vitamins and supplements. This is something I am sure Prevention Magazine (also very anti-medication) likes a lot.

The problem is that there is limited data (with the exception of the DASH diet) for diet and exercise as a potential replacement for medications to control chronic diseases such as high cholesterol, hypertension and diabetes. This is not to say that diet and exercise is not important. On the contrary, it is the cornerstone of management of many chronic medical conditions. However, once the disease is established, it is very hard for diet and exercise changes to eliminate the need for medications. In addition, vitamins and supplements have problems of their own. Some supplement may not be safe, and even common vitamins like C and E may actually be harmful (see here).

The bigger issue of polypharmacy is not that medications are killing you, its that we are not looking closely enough at potential redundancy and interactions with medications. We currently have a discoordinated health care system with no single source of patient medical information. For the elderly patient who is seeing multiple specialists, those doctors rely on the patient's history of what medications he or she is or is not taking. A shared electronic medical record (EMR) would keep patients and physicians up to date and could automatically warn of potential interactions, but this will cost a lot of money. However, even if an EMR were available and ubiquitous, this alone would not be enough. It takes time to talk to patients about their medications and side effects. In the article, the author's mother was give four asthma medicines for a cough that was not asthma but a side effect of another medication. A few extra minutes by a primary physician and some simple office based testing could have picked up the problem. However, we have heard many times how primary care physicians are struggling.

One should note that Dr. Neel is not just a friendly, knowledge pharmacist at your local CVS. Dr. Neel is a consultant. He charges a retainer fee of $300.00 per year and $115.00 per hour. Now we have concierge pharmacists to go along with our concierge physicians. Siri Carpenter, the author of this piece forgot to mention this small fact.

Wednesday, November 12, 2008

Avandia Vindicated (Again): The Diabetes Conspiracy Part II

Late this morning, results from the APPROACH study were presented at the American Heart Association. Unlike the JUPITER study which I blogged about the other day, this study seems to have generated little press (at the time of this posting only AP press and MSNBC). However, already the press makes it seem like Avandia remains a bad drug, with headlines stating:

"Controversial diabetes med doesn't slow plaque"

I recently posted (The Diabetes Conspiracy (Part I) ) that Avandia and Januvia were taking the heat for increasing the cost of diabetes care, yet no one seemed to comment on the newer insulins which in addition to contributing about equally to the increase in cost of diabetes care, were being prescribed at a much faster pace then either of the two newer diabetes pills.

I have previously blogged about the Avandia scare (for details see Avandia Vindicated! ). Briefly, in May 2007, Dr. Steve Nissen published a highly publicized, as well as highly criticized meta-analysis of 42 studies stating that Avandia caused heart attacks. The study was published ahead of press in unprecedented fashion, and congressional calls for investigation were sounded immediately (almost as if the politicians knew in advance). The FDA found something different. Though their similar analysis did find an association with myocardial ischemia (not heart attack) with Avandia, it was only when Avandia was compared to placebo and not other diabetes drugs. In addition, their analysis of three large, randomized prospective studies (RECORD, ADOPT, DREAM) and several large databases of patients showed no evidence of a problem. Since the FDA's analysis, several other large diabetes studies in which patients took Avandia have been published, all showing no risk of heart attack with Avandia. 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 APPROACH study was a prospective, randomized, double-blind study which looked at 672 diabetic patients who needed to have an angiogram or angioplasty (thus, high risk for heart attack). They looked at one of the coronary vessels that was not going to be intervened on and measured the amount of plaque build up. Half the patients got Avandia and the other half got glipizide, an older, generic diabetes medication. Patients took either drug for 18 months, and by the end of the study, compared to glipizide, patients on Avandia had an increase in their high-density lipoprotein (HDL) (or good cholesterol), lowering of their blood pressure, lowering of their triglycerides and lowering of their CRP (which thanks to JUPITER seems even more important). There was a small increase in low-density lipoprotein (LDL, “bad” cholesterol) in patients taking Avandia. The investigators used intravascular ultrasound (IVUS) to measure the buid up of plaque. They looked at change in % atheroma volume (primary endpoint) as well as change in total volume, and change in the worse segment. The patients taking the older diabetes medicine had an increase in there % atheroma volume (0.42%) (more plaque= bad) where the patients taking Avandia had a decrease in their % atheroma volume (-0.22%), but this was not statistically significant (p=0.12). Though there was similar non-significant reductions in the worst segment, there was a decrease in the total atheroma volume which as statistically significant.

Technically, this is a "negative" study because the primary endpoint was not found to be statistically significant. However, this is not "bad news" for Avandia, nor does it mean it is a bad drug.
1. Patients on the older generic drugs had increase in plaque build up, Avandia patients did not. The p value of 0.12 means there is an 88% chance these findings are true. By convention, we only accept the results if there is more than 95% chance. However, given the statistically significant decrease in atheroma volume as well as positive changes in in BP, CRP, etc. if anything it would appear that Avandia leans toward reducing risks for heart attacks. Though this study was small, these patient were all at high risk for heart attacks (they were having angioplasties!). Yet, there was no difference in heart attacks in patients taking Avandia. Thus, this study provides even more evidence that Dr. Nissen's flawed meta-analysis was completely wrong!

2. The patients on the older diabetes drugs had more hypoglycemia. I will blog on this in more detail, but hypoglycemia is not trivial. It can be life threatening. Avandia does not cause hypoglyccemia.

3. A virtually identical study was done with the other TZD on the market, Actos. The PERISCOPE study had almost identical findings. In that study, the patients on Actos had a 0.16% decrease in their % atheroma volume (numerically not as good as Avandia, but probably the same). However, the patients taking glimepiride (a similar, older, generic diabetes medicine) has a 0.73% increase in % atheroma volume (the patients on the generic diabetes medicine in PERISCOPE had more plaque build up the the patients taking the generic medications in APPROACH). However, this difference was statistically significant. It is possible that APPROACH was a "negative" study and PERISCOPE was "positive" because the patients on the older medicines did worse in PERISCOPE. Drug companies and diabetes experts will likely debate this for years. The PROACTIVE study showed that Actos actually prevented heart attacks in strokes in patients with high risks for diabetes. My point is not to say whether Actos is or is not different from Avandia. The point is that the study designs and findings of both studies were similar, suggesting that if anything both Actos and Avandia would protect you from having a heart attack, and not cause one.

Already, the media is quoting our old friend Dr. Steven Nissen on the findings of APPROACH. He claims that these results "give one more reason" to use Avandia with caution. Oh, by the way, do you know who the lead investigator for the PERISCOPE study was? Yep, Dr. Nissen. Guess who funded his research? (Hint: Takeda makes Actos). Nissen did another meta-analysis on Actos published in JAMA that unlike his NEJM Avandia meta-analysis, found no problem with Actos. Many of those patients in that analysis came from the PROACTIVE study. Please note that Takeda gave Dr. Nissen and friends $25,000 to help analyze the results.

Bottom Line: It's too early as I blog to judge media reaction. They may give this study very little attention. What attention this study does get will make it sound like this is yet another problem for Avandia, which will be reinforced by comments by Dr. Nissen. The reality is that though the primary endpoint of APPROACH was not statistically significant, both Avandia and Actos likely prevent, not cause heart attacks. One should be very skeptical of Dr. Nissen's determination to take down Avandia. He is just one of several players in the Diabetes Conspiracy.

Sunday, November 9, 2008

Jupiter is Out, and the News is Good!

I am writing this within hours of the release of the Jupiter study. Already, this is hitting the media at WSJ and CNN, but expect more because this is big news. Looks like DB beat me to the punch, but he seems equally impressed

We participated in this study, so I may be a little biased, but the results are pretty impressive. The study looked at 17,802 patients from all over the world (including the US). The study gave half the patients 20mg of Crestor and the other half placebo. These patients relatively normal cholesterol levels and normal risk for heart attacks, except for an elevated C-reactive protein, or CRP, which is known to be associated with an increased risk of heart attack and stroke. The study was planned for 4 years, but stopped early at 1.9 years when the found that there was a clear benefit for those taking Crestor, and continuing the study would be unethical. The study was stopped a few months ago but the results were presented today and released ahead of press in the New England Journal.

The study found that Crestor reduced the risk of heart-related death, heart attacks and other serious cardiac problems by 44%. This pretty impressive given that these patients under current guidelines would not normally be candidates for taking cholesterol medication.

As evidenced already by the WSJ and CNN post, the message to the public will be 1) this may expand the use of statin medications for people who would otherwise not take them and 2) we need to be cautious before we do this.

Here's a few interesting things that have/may not come out.

1. Crestor is safe. Crestor, which is the most potent statin available on the market had the misfortune of launching just as Vioxx was pulled from the market. When David Graham from the FDA testified in front of congress, he named 5 drugs to potentially be worried about, Crestor being one of them. Dr. Sidney Wolfe, from Public Citizen had already petitioned the FDA not to approve Crestor, and asked for its immediate withdrawal from the market soon after launch. In a 36 page document, the FDA responded to Dr. Wolfe, essentially stating that Crestor was safe. However, the group continues to list Crestor among the worst pills to take.
If anything, this study clearly shows that Crestor is safe. Despite its potency, in a study of almost 18,000 patients, there were no differences in side effects between those that took 20mg and those taking placebo. You read that correctly, no differences. No differences in myopathy, elevated liver enzymes, kidney problems, etc. There was one patient that died of rhabdomyolysis (a very rare, but severe complication of statin medications). However, this patient was 90-years-old and had influenza, pneumonia, and trauma-induced myopathy; and this occured after the study was over.

2. Benefit of treating CRP alone was substantial. There were 142 heart attacks or cardiovascular related envents in the almost 9000 patients given Crestor 20mg, and 251 in the placebo group. This translates in to a number needed to treat (NNT) of 82. In otherwords, you would have to give Crestor 20mg to 82 patients with normal cholesterol but a high CRP for nearly 2 years in order to prevent one of these events. Some will argue that this impact was not substantial. With Crestor at about $3.45 a day, it would cost almost $200,000 over 2 years to prevent such an event. This may seem like a lot, but for mammography, some have calculated the number needed to screen to prevent one death is 781 women, and at a cost of $150 per mammogram, this comes to almost $120,000 which is not that far off.

3. These patients had a low risk for heart attack or stroke. The patients in this study had about a 6% risk of having a heart attack or stroke in 5 years using Framingham calculations. Indeed, the placebo group was found to have a risk of heart attack of less than 1% in the 1.9 years of the study. The mean LDL at baseline was 108mg/dL and current guidelines would have recommended an LDL less than 130mg/dL, with an option of lower than 100. Most physicians would not treat these patients with a medication. Thus, a 44% reduction (absolute reduction about 4%) is pretty impressive and does indeed suggest an expanded role for statins, or at least the need to check CRP.

4. Would a generic be just a good? One could extrapolate that using a generic statin such as simvastatin (generic for Zocor) could do just as well, but at a lower cost ($1 a day). There are several problems with this. First, patients in the study got a 50% reduction in their LDL cholesterol and a 37% reduction in their CRP with 20mg of Crestor. Best case scenario for simivastatin would be 80mg with up to a 47% reduction. However, one thing to consider is that the higher you go in dose, the more likely you are to get side effects with medicine. 20mg of Crestor is half the maximal dose (much of Dr. Wolfe's concern arose from 80mg of Crestor, which did have some side effects, and is why it is not available). 80mg of simvastatin is the maximal dose and very likely to cause side effects. Interestingly, all the studies looking at CRP and vascular changes seem to be in the studies using the higher doses of the potent statins like Lipitor and Crestor. Thus, though a few dollars might be saved, it is not clear that the benefit would be the same and you would likely end up with more side effects.

5. What about diabetes? Not sure whether the media will pick up on this, but they did find that physician report of diabetes was increased in the Crestor group (270 reports of diabetes, vs. 216 in the placebo group; P=0.01). This might seem a concern; however, these were physician reports without confirmation. When looking at the study lab values, there were no significant differences with respect to the fasting blood glucose level, and the A1c level was pretty much the same (5.9% and 5.8%). There is no biologically plausible reason to suspect Crestor as a cause of diabetes. However, both groups had a 41% prevalence of metabolic syndrome, which is a pre-diabetic state. Thus, it is not surprising to find an increase in diabetes in both groups.

Bottom Line
This is compelling data and will likely change guidelines. The anti-statin, anti-pharma folks will try to shoot this one down, but the data is pretty solid. If you are a man over 50 or a woman over 60, you should definitely ask your doctor to check your CRP if you cholesterol is relatively normal, and you would not otherwise be a candidate for cholesterol lowering medication. If your CRP is elevated, I think Crestor 20mg is a good option, since it is not clear that other medications (specifically simvastatin) would provide similar benefit.

Wednesday, November 5, 2008

The Diabetes Conspiracy (Part I)

Avandia continues to get bashed by the press, though I have tried hard to defend it. Today's firing of 1800 GSK employees may have something to do with the declining sales of this product.

The latest bashing has to due with cost, and comes from a study in the Archives of Internal Medicine that revealed spending on diabetes medication has increased by 87% (almost double) in the past six years, from $6.7 Billion in 2001 to $12.5 Billion in 2007.

This was not only picked up by the mainstream media (MSNBC) but the medical blogsphere as well. Dr. Kevin Pho of Kevin MD noted that:

"these drugs (Avandia and Januvia) are markedly more expensive than the recommended first-line generic medication metformin.It's no wonder than spending on diabetes drugs has doubled to $12.5 billion over the past 6 years. Unless there's a medical contrindication, doctors shouldn't be reaching for these brand name medications first."

Kevin's comment seems to make sense. On his blog he also linked to Pizaazz' post Diabetes Drug Costs on the Rise which stated:

"The study investigators noted that the newer drugs Januvia, Avandia and the wildly popular Actos were prescribed in 28% of all doctor visits by the end of the study period." Pizaazz included this quote from Dr. David Nathan, who is Chief of the Diabetes Unit at Massachusetts General Hospital:

“We need to pay attention to this...if you can achieve the same glucose control at lower cost and lower side effects, that’s what you want to do.”

Sounds like expensive drugs such as Januvia and the thiazolidinediones (TZD's) like Actos and Avandia are just expensive pills made by the evil drug companies, which are doing nothing more than doubling the cost of medicines for diabetes. But hold on....

Before we (once again) malign branded prescription pills for diabetes, lets look beyond the sound bites and see what the data is really telling us about the changes in diabetes and diabetes care.

First, the number of patients with diabetes in the United States has increased. The study quotes 14 million diabetics in 2000 which increased to 19 million in 2007. This is due to the fact that as a nation we are becoming more and more overweight and obese, and thus more likely to get diabetes. Thus, an 87% increase in spending can be partially accounted for by the 36% increase in incidence of diabetes. If we are going to start throwing around blame, then we need to include McDonalds, Starbucks, Microsoft, etc.

Second, we need to look at the overall trends in diabetes. Metformin has replaced sulfonylurea as the most commonly prescribed pill for diabetes, likely due to better results with fewer side effects. The TZD's are a new class of medications that have slowly risen since their introduction, but are still prescribed less the the other two medications. Another less mentioned trend is the use of insulin, which started to decline a few years ago, but it has recently made a resurgence. More importantly the older (cheaper, generic) insulins have been almost entirely replaced by the newer, more expensive insulins. Finally, two new drugs (Byetta and Januvia) have been more recently introduced to market and are starting to gain acceptance.

Let's looks at the trends and costs of ALL of these products over the last 6 years, based on the data from the study.

Lispro (a very short acting insulin) increased from 2% of visits in 2001 and $0.4 Billion, to 7% and $1.4 Billion in 2007 (more than triple the use and cost)

Lantus (a very long acting insulin) increased from 2% and $0.1 Billion in 2001 to 12% and $2 billion in 2007 (six times the use and 10 times the cost)

The TZDs (Avandia and Actos) did peak in 2005 at 34%, but their use in 2007 is now the same as it was back in 2001 and prescribed at 28% of visits. The money spent doubled from about $1.9 billion in 2001 to $4.2 billion in 2007.

Per the study's estimates TZD's, Lispro and Lantus all cost $160, $156 and $123 respectively, which is not that much different. Thus, of the extra $5.8 billion dollars we are paying more for diabetes, $2.3 billion is coming from the TZD's, and $1.9 billion is coming from the newer insulins.

Januvia and Byetta, new types of drugs which I am calling (and thus hopefully coining the term) glucose regulators were new or non-existent in 2001 and they are now prescribed at 10% and 3% visits respectively for a combined additional $1.5 billion. Though Januvia is prescribed three times more often than Byetta, Byetta ($205) costs about 30% more than Januvia ($160-about the same price as new insulins and TZD's). Of note, Byetta is currently a twice daily injection, but will soon be available as a once weekly injection which may increase demand for this product incredibly.

Thus, though spending on diabetes medications has nearly doubled in the last six years (in part due to increased number of Americans with diabetes), the newer and more expensive insulins have contributed about as much to this as the TZD's like Avandia. However, unlike the TZD's of which overall prescribing hasn't changed, the newer insulins are being used 3 to 6 times more and that trend is likely to continue to rise. Furthermore, the introduction of Januvia and Byetta combined is still less of a factor than the newer insulins.

Where's all the negative press about insulin? Why does Avandia always get the bad rap? Why are the experts (like Dr. Nathan) not also calling for an immediate reduction in these newer insulins since they are equal contributors to the rising cost of diabetes, are rapidly increasing in their number of prescriptions where Actos and Avandia are stable, and they are no more effective (though they do have fewer side effects) then the older, generic insulins? Is Dr. Nathan "paying attention?"

More to come........

What can President Obama do about health care right now?

The results of yesterday's election were stunning. Regardless of who you supported, most should be able to appreciate the historic moment that just occurred. President Obama will have many daunting challenges ahead, including fixing our broken health care system. Not only will this not be a difficult task, but it will also not occur overnight. However, doctors and patients are struggling now. With changes in the make up of congress and the momentum from the election, here are three things that President Obama could do immediately after January's Inauguration to make some substantial changes right now.

1. Pay physicians for talking to patients. Our study which looked at factors associated with medical students career choices showed that only 2% wanted to go into primary care internal medicine. Though huge student debt and lucrative salaries in fields like dermatology and radiology may contribute, most students who applied to medical school did not do so in order to drive a Mercedes or live in a mansion. One of the main reasons that students shy away from primary care has to do with the burdens of practice, which is largely due to the way in which primary care is reimbursed. The medical home has been proposed as one method to deliver coordinated care, improve quality as well as change the way primary care services are reimbursed. However, agreeing on exactly what this will look like and how it will become mainstay practice may take some time. In the mean time, how about some immediate legislation that increased the amount of money physicians get for the time time they spend with patients, without ridiculous codes and other documentation requirements to get reimbursed. This should also apply for non-visit related time such as emails, phone calls, and filling out forms/paper work. This is not a solution for solving our delivery system crisis, but would have an immediate impact.

2. Tort reform. There is agreement on both sides of the aisle on this issue, so let's pass something quickly. The main problem is that bad outcomes do not generally result from malpractice, but patients need some kind of compensation when things do go wrong. Doctors order more tests because of malpractice fears. Not only does this increase the cost health care, but probably results in more harm to patients, since added testing (especially in patients who don't really need it) usually leads to complications from further testing and treatment. No-fault insurance and/or an impartial hearing before a case goes forward have been proposed solutions. Even if a long term solution takes some time, immediate caps on pain and suffering could help now.

3. National formulary. Whether you favor universal health care, or fear "government run" health care, negotiating drug prices with the pharmaceutical industry is a no brainer. Medicare, Medicaid and the VA get the best deals on drug prices because they have the volume of patients that the government can use in their negotiations with the drug companies. You could even keep your private, for-profit health insurance, but have your drug benefits "carved out." Allowing the government to negotiate drug prices on your behalf could immediately cut the price we spend on pharmaceuticals. We could create a sliding scale based on income regarding what an individual would pay for generic and brand named drugs. Even if it takes some time to cover the 47 million Americans without health care, we should be able to get them prescriptions pretty quickly.

Monday, November 3, 2008

Did Your Doctor Get it Right?

The latest from MSNBC is an article about questioning your physicians diagnosis called Did your doctor get it right? The premise is that commonly presenting symptoms are not always what they seem and your physician may mistakenly treat the wrong condition. Persistent cough vs. asthma, anxiety vs. arrhythmia, sinus infection vs. migraine, post nasal drip vs. Laryngopharyngeal reflux and urinary tract infection vs. interstitial cystitis are the five diagnosis that are discussed.

Stacey Colino, the author of the piece who is not listed as a physician or health care professional invites patients to "sleuth out what’s actually making you sick so you can find the right remedy and feel better fast."

I don't have any problems with the factual material of the article, other than the weight of the evidence (migraines and laryngopharyngeal reflux are probably missed more frequently, whereas most persistent coughs in adults are not likely new onset asthma). However, the notion that your doctor has no clue, and you should be your own detective is a unwise suggestion.

Physicians, myself included, do not get all diagnoses right the first time. That said, figuring out your own disease on your own is probably not the best alternative. Medicine is tricky. I see sinusitis and upper respiratory tract infections every single day, and they all present slightly differently in different patients. One of the interesting things about primary care is how unique everyone's "common" illnesses are; both the diagnosis and how the illness affects patients' lives. In addition to years of training, what a physician has is the years of experience to sort out what the actual problem may be. This experience can not be learned just by completing medical school, and certainly not on the Internet.

Instead of trying to "solve the case" case as "doctor" Colino suggests, here are some tips to help you and your physician arrive at the correct diagnosis when you have a medical problem.

1. Don't leave anything out. In medical school, we train our students to ask the right questions to help ascertain all the clues to determine the correct diagnosis. However, we can not read minds. If there is something else bothering you, regardless of whether or not you may believe it is connected, please mention this. This could be as simple as stress at work, a change in diet, a seemingly mild and unrelated symptom. Your physician may reassure you that indeed this is not likely related, but it is important to mention everything that is going on.

2. Understand your diagnosis. Once a diagnosis is made, you should not only understand what you have, but why your physician feels this way and why he or she is recommending the treatment given. Not only is this important so you can understand what is happening, but also because a misunderstanding or correcting the physician's perceptions of your illness may lead to the correct diagnosis.

3. Have a plan. Your physician should not only tell you what you have, but also when you should expect to feel better and what things to look out for that could possibly go wrong or lead to a different diagnosis. Antibiotics typically work in a day or two, so if you are not feeling substantially better, there could be a problem. Conversely, upper respiratory infections caused by viruses can take up to two weeks (sometimes longer) to resolve. If patients know what to expect, they won't be trying to solve their own medical mystery when things haven't improved quickly.

4. Communicate. Problems occur when patients don't communicate with their doctors. The article would suggest for example that if your cough isn't going away you might have asthma. You might look this up on the Internet and then either try a relative's medicine or take some over the counter Primatene Mist. This would be a huge mistake. As above, you should have a plan. When that plan doesn't go as expected, don't just ditch your doctor and solve your own problem. Call the physician and let them know you are not getting better. Response to treatment helps confirm a diagnosis or suggest a new one. In this specific case, I would probably re-evaluate the patient, possibly order more tests such as a chest X-ray, and try alternative medications (which are generally safer then over the counter meds and using someone else's prescriptions).

Wednesday, October 22, 2008

Pharma & Pharmacy: CVS and Merck Team Up to Sell Drugs!

Let me start off this post by stating though I may be critical of certain practices of certain drug companies, I am by no means anti-pharma. Though the pharmaceutical industry is one of the most profitable industries, they bring valuable products and research to the public and the issues surrounding big pharma are far more grey then black and white in my opinion.

That said, I was somewhat shocked when I received a letter from CVS/Caremark about one of my patients. The patient was identified by name, date of birth and medication. The letter stated that this patient was identified by "through CVS Caremarks prescription claims data as having one or more prescriptions filled for metformin or a thaizolidinedione as their only treatment for diabetes." Actos and Avandia are the two thaizolidinedione availabe in the US, and metformin is the most commonly prescribed diabetes pill.

I have received similar notifications before, but usually because patients had only filled one or two prescriptions in a 12 month period for a medication (like the ones above) that they are supposed to be taking every day, thus alerting me to the possibility that my patient may not be taking their medications.

However, this letter was different, because I knew this patient was very compliant with all of his pills. This letter went on to say that I should consider prescribing Januvia for my patients (like the one listed) whose diabetes may not be under control. The bulk of the letter discussed information about Januvia. In very small print at the bottom of the page, it said "funding for this communication was provided by Merck & Co." You don't have to by a doctor or health care industry insider to figure out which company make Januvia.

I have no problems with Januvia. I actually will add this medications to my patients who are on metformin and/or a thaizolidinedione, who are not at a goal hemoglobin A1c of less than 7%. However, it is disturbing that the pharmacy is pushing a drug on behalf of a drug company. CVS/Caremark fills or manages more than 1 billion prescriptions annually through its approximately 6,300 CVS/pharmacy stores across the country. Ironically, the Wall Street Journal just reported that Merck just cut 7200 jobs. Perhaps they feel they can fire their reps, and let CVS and their employees sell their products. This is a bad mix, because both companies profit from prescriptions filled.

It is now well known that the drug companies collect prescribing data on physicians, but they only know what drugs physicians are prescribing and not who they are prescribing them for. Pharmacies obviously know what the doctor prescribes and which patients get it, but it is a privacy violation to share this with the drug companies. By funding promotional material through the pharmacies, the drug companies can target physicians at a patient specific level, bypassing patient confidentiality issues.

Though today it was only a letter promoting a drug attached to a patient who might potentially need it, what's next? Will I be receiving promotional calls from my local CVS pharmacy which seems like a professional to professional communication, but is really a disguised sales pitch? Will the retail pharmacist get a pop-up message when a patient is refilling a certain medication to ask their doctor to prescribe another? We are a free market society, and drug companies have a right to market their products, but the letter I received today is just plain wrong. It might even be illegal.

Tuesday, October 14, 2008

Open Enrollment Tip: Make Sure Your Doctor Can Still See You

A pair of articles in the Wall Street Journal and the Washington Post talk about and tips on saving money spent on health care and advice for open enrollment respectively.

I basically agree with all suggestions. WSJ's four tips include paying attention to open enrollment info at work (don't assume you will automatically keep your coverage by doing nothing), consider opting for higher co-pays and lower premiums if you don't see the doctor that often, signing up for a flexible spending account if offered, and inquiring about any company wellness incentives. The Post similarly suggests not to shop on premium alone and looking into wellness programs as well as figuring out your yearly out of pocket expenses, understanding your plan such as savings for in-network providers, and saving money by using mail order prescriptions.

However, one thing not mentioned in either story relates to changing insurances and still seeing your same doctor. The medical blogsphere (and even mainstream media) is filled with stories about how difficult it can be to find a primary care physician. One of the reasons is that many physicians, especially in metropolitan areas, have stopped taking some or all insurances. This is due to that fact that for some insurances the reimbursement rates are so low, physicians actually lose money by seeing patients in certain plans. As a physician in a university faculty practice that takes virtually all insurances, so many of my newer patients are from physicians just blocks away that simply stopped accepting these patients' insurances. Our division of General Internal Medicine has actually been closed to new patients for almost two years, simply because we don't have enough doctors to see all the patients we currently are responsible. (A closed university practice was once unthinkable and is a strong indicator of what a true primary crisis we currently have).

Before switching insurances, make sure your physician takes that insurance. Don't trust the information that the health insurance company hands out via your HR informational session. These paper copies are typically out of date. Call your physician's office business manager directly. Even if they currently accept the insurance, ask if they have any plans to drop it in the near future, as well as if they are currently accepting new patients on this insurance and if not, will they "grandfather" you in. When you sign up for a new insurance, you are considered a new patient. Though your doctor is legally obligated to continue your care, he or she is not legally obligated to accept your new insurance if they are closed to new patients. Though most physicians would unlikely "drop" current longstanding patients who switch to a cheaper insurance plan, it doesn't hurt to ask before you switch.