Conservatives Should Read Ezra Klein

I try not to get too polictical on my blog. I consider myself a moderate. I supported passage of the health care reform bill, but mainly because if it had failed, in my opinion, discussions of true health care reform would be stalled for another decade. Though there are some good things about the current legislation (removal of pre-existing conditions for example), there is nothing really that addresses the escalating costs of health care.

Though most political news recently has been about taxes, health care reform is in the news again today, due to a judge's ruling regarding the consitutionality of the individual mandate. You can read the NY Times or Washington Post's coverage. Pundits on the left and right will likely once again discuss their positions on both sides of the health care debate.

However, journalist (and notably liberal talking head) Ezra Klein had some very interesting comments that those on the right would be wise to take note of. In addition to pointing out that the President Obama was the one opposed to the individual mandate during the primaries and criticized Hillary Clinton for supporting this, he states:

The individual mandate began life as a Republican idea. Its earliest appearances in legislation were in the Republican alternatives to the Clinton health-care bill, where it was co-sponsored by such GOP stalwarts as Bob Dole, Orrin G. Hatch and Charles E. Grassley. Later on, it was the centerpiece of then-Gov. Mitt Romney's health-reform plan in Massachusetts.....It was only when the individual mandate appeared in President Obama's legislation that it became so polarizing on the right..... The individual mandate was created by conservatives who realized that it was the only way to get universal coverage into the private market. Otherwise, insurers turn away the sick, public anger rises, and, eventually, you get some kind of government-run, single-payer system, much as they did in Europe, and much as we have with Medicare. If Republicans succeed in taking it off the table, they may sign the death warrant for private insurers in America: Eventually, rising cost pressures will force more aggressive reforms than even Obama has proposed, and if conservative judges have made the private market unfixable by removing the most effective way to deal with adverse selection problems, the only alternative will be the very constitutional, but decidedly non-conservative, single-payer path.

In other words, the only way that we can afford health care coverage for most Americans (whether it be provided by the government or the private sector) is if everyone pays something to have it, and the fiscally conservative Republicans knew this, which is why they suggested this in the first place. Interesting.

Don't Call Me for A Prescription for Your Aspirin

As reported by MSNBC, the federal government will no longer allow flexible spending accounts (FSA's) to be used for over the counter medications, without a prescription. FSA's, which are offered by many employers, allow you to use tax free dollars for medical expenses that aren't covered by your insurance. FSA's are a great idea and can be used for things like eye glasses, dentistry, or even nicotine patches for smoking cessation.

The people most likely affected by this rule are those that take over the counter medications on a regular basis. Examples of such medications include pills for allergies, heartburn , aspirin for heart attack prevention, and smoking cessation aids. Medical supplies like insulin syringes and crutches, though sold over the counter, are exempted.

Now, you might think, "no big deal, I will just call my doctor and ask her to call in a prescription for a baby aspirin a day." This would certainly solve your problem, but it adds to your physician's problem and is a perfect example of the problems with the reimbursement system for health care, particularly for primary care.

If you are not aware by now, procedures get reimbursed much more than just talking to patients, which is why cardiologists make so much more than primary care physicians. However, anything that doesn't happen in an office visit is generally not reimbursed at all. Primary care physicians can be great managers of your health care, done in a way that it convenient for you, and at a low cost- phone calls, emails, forms, etc. Problem is that the few minutes spent on you add up and take a whole lot of time. None of which is reimbursed by health care insurances under the current system. One doctor started adding these things up, and of the 50-60 hours each week the doctor put in, each day they:

Handled 23.7 phone calls.
Answered 16.8 e-mails, mostly dealing with test result interpretations.
Dealt with 19.5 lab reports, 11.1 imaging reports and 13.9 consult reports.
Issued 12.1 prescription refills, excluding those issued during patient visits

None of these are reimbursed.

Now, here's the real kicker about asking your doctor for an aspirin prescription. Not only are you compounding this problem, but you are also doing it not for better care (or any care for that matter), but so you can save money!
Finally, consider this:
Even though you can easily go to CVS and get aspirin on your own, if your doctor writes you a prescription for aspirin, legally speaking it is a whole different ball of wax. By writing a prescription, even if only for an aspirin, your doctor is rendering medical care. He is required by law to accurately document this. He is also liable for this care. If you had an adverse reaction to the aspirin prescribed, you could certainly sue.
Thus, by asking for a prescription for an aspirin, you are asking for the doctor to deliver care which he is liable for, which he will not get paid for, which (when added up for each patient) will take time away from true patient care and for the sole purpose of you saving yourself a few bucks.

Now, one of the reasons that primary care physicians have gotten into the mess that we are in is because we generally want to do what's best for the patient and have been delivering this kind of free care for a long time. We actually were glad to do it, and only started complaining recently when what we got paid for actual care kept declining while our specialist colleagues kept getting more money, and our paper work started to increase. Many of us (probably including myself) will likely grant these requests without a complaint.

The point of this post was not to prevent your from requesting an OTC prescription from your physician for tax purposes. After all, the economy is still horrible and many patients truly need daily medications for allergies and heartburn that are quite expensive. The point is that are entire health care reimbursement system must change, and must change very soon. A few requests for OTC prescriptions for FSA's on top of a 23% Medicare cut might be all it takes for a primary care physician to stop practicing medicine altogether.

Spiriva for Asthma?? Not so fast.

There is a lot of press about a study just published in the New England Journal of Medicine that shows that adding tiotropium (Spiriva) to an inhaled steroid might have benefit in asthmatic patients. This study is creating a lot of buzz due to recent concerns of ICS/LABA safety and might prompt doctors and patients to start switching (some already have before this study came out). However, this would be a HUGE mistake.

The study was a small study of 210 patients that compared the addition of tiotropium (Spiriva) which is a a long-acting anticholinergic inhaler currently only used in the treatment of chronic obstructive pulmonary disease (COPD) to an inhaled corticosteroid (ICS), and compared this to
doubling of the dose of the ICS or adding the long-acting beta agonist (LABA) salmeterol.

The primary endpoint of the study was improvement in morning peak flow, which they found that adding tiotropium increased by 25.8 liters per minute (P<0.001) as compared to doubling the dose of the ICS. There was also improvement in secondary outcomes such as lung function as measured by FEV1, which showed an improvement of 0.10 liters (P = 0.004). In addition, when comparing additng tiotropium or salmeterol to ICS (the study was designed to show tiotropium was no worse), they found tiotropium slighlty better than salmeterol in terms of morning peak flow (6.4 liters per minute (P<0.001)) and not significanlty different in lung function (FEV1 difference of 0.11 liters).

With some safety concerns regarding the use of LABA's, (I have blogged about this before and the bottom line is that if taking with an ICS, there seems to be no problems with LABA's) the New England Journal article might tempt doctors to use tiotropium instead of a LABA in asthmatic patients, if the evidence suggests that the benefit is similar between Spiriva and Salmeterol. However, making this leap would be dangerous for several reasons.


1. Almost all the data supports the use of LABAs. This is an intriguing but small study. Clearly more studies are warranted. However, the question of adding LABA's vs doubling the ICS dose has been extensively well studied. The best source is the unbiased Cohrane Review. Their review included 48 studies (15,155 participants including 1155 children and 14,000 adults). In looking at the morning PEF (the New England Journal article's main end point), the Cochrane group found that adding LABA to an ICS (compared to doubling the ICS dose) showed a 16.30 L/min improvement from baseline. This is similar to what was found in the New England Journal study. In looking at FEV1, the Cochrance group found an improvement of 0.08 (CI 0.03 to 0.13), which is closer to what was found with Spriva and much higher than what was seen in the New England Journal study. In other words, in looking at 48 studies with thousands of patients, ICS + LABA performs a little better than it did in the New England Journal study, although it does not clearly beat the numbers of tiotropium.

2. There is no data on outcomes such as exacerbations. A small bump in peak flow or lung function is meaningless if patients are still getting sick. The main goal of asthma treatment is to prevent exacerbations. The New England Journal study was too small to show this. However, the Cochrane review clearly shows that adding a LABA to and ICS, compared to doubling the dose of the ICS clearly prevents exacerbations. They showed a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73.

3. There is no ICS/tiotropium combination inhaler (yet). One of the advantages to ICS/LABA combination inhalers is that both medications come in a single inhaler. This is critical. As mentioned, the LABA safety issues seems to occur when patients take LABA's without an ICS. This makes sense because even though the bronchodilator might make patients feel better, not treating the disease (inflammation) can lead to serious problems down the line. Because of this, the FDA recently recommned that children who take ICS and LABA's together only take them in the same inhaler. The worrry is that if the two inhalers are used separately, patients are at risk of only taking the brochodilator. Because the bronchodilator makes patients feel better, they are more likely to be adherenct to this inhaler than an ICS, which has effects that patients don't immediately notice. This same concern would be true of tiotropium, which is also a bronchodilator. However, ICS/anticholergic combination inhalers should be available soon. Studies will be now needed not only in COPD, but also in asthma to see which regimen produces the best benefit.

Bottom Line: This is an exciting study. By showing tiotropium has potential benefit in asthmatic patients, it may give clinicians and patients an additional tool to treat this disease. The study shows that use of tiotropium in asthma clearly warrants more research. However, doctors and patients should not start taking ICS and tiotropium over ICS/LABA, since the data (especially regarding exacerbations) is just not there.

Study 175 and the Need for Comparative Effectiveness Research

Though I am not going to say that the New York Times lied, they either purposely and grossly misrepresented the truth or did a horrible job of reporting. In their article "Diabetes Drug Maker Hid Test Data, Files Indicate" the Times states that Avandia maker GSK "secretly began” a study which ”provided clear signs that it (Avandia) was riskier to the heart.” In fact, the study in question, called study 175, was a small, short study, that had no cardiovascular outcomes (only lipid data) and was not a comparison of Actos and Avandia. In fact, there were no patients taking Avandia in this study! In addition, from pages and pages of documents, the Times took an out of context comment about the study (a GSK memo which read that study 175 shouldn't see the “light of day”) to make their charges sound even more damning. The New York Times should be above this kind of sensationalist journalism.




Let me give you a breakdown of study 175, why it was done, what it showed, and most importantly how this relates to the need for comparative effectiveness. You can read the official GSK statement about study 175 here, or look at the data yourself, which comes from a letter to the FDA from Senator Grassley (via Pharmalot).





Both Avandia (GSK) and its competitor Actos (Takeda) came out around the same time in the late 90's. Both were insulin sensitizers or TZD's, a new class of drugs for diabetes; a disease which hadn't seen any new drugs in a while. Not surprisingly, the two companies with their respective products were pretty competitive. The Takeda drug reps were usually quick to point out that though both products improved diabetes control, Actos did a better job on lipids. (Note that in addition to improving diabetes, the TZD's have a positive effect on lipids). The Actos people were able to make this claim because in their studies, Actos lowered triglycerides or fats by about 9% and in the GSK studies, Avandia didn't have much of an effect on triglycerides. This is a common tactic used by drug reps and breaks a cardinal rule of evidence based medicine: you can not compare products across studies, because in each study the populations and circumstances might be different. The only real way to make a comparison is in a head to head comparative trial. (This point remains very relevant, because the recent FDA advisory committee somehow concluded that Actos was safer than Avandia without one head to head trial!)






However, GSK noted an additional flaw in the Takeda claims. In the Actos studies, the patients started out with an average triglyceride level of about 260 mg/dL, where the patients in the Avandia studies had baseline triglyceride levels closer to 180mg/dL. In other words, if you start with worse numbers, you are more likely to show a bigger improvement. How well would Actos do on triglycerides in patients with closer to normal levels of triglycerides (normal is less than 150mg/dL)? One way to find out would be to do a head to head study comparing Actos to Avandia in patients with similar cholesterol and triglyceride levels. GSK could have certainly done this, but what would happen if the GSK study proved that Actos did indeed work better on triglycerides? Before spending a substantial amount of time and money on a study that could ultimately hurt the company, GSK did study 175 which looked at lipid levels in patients taking Actos who started with relatively normal cholesterol levels. Though they compared this to historical Avandia data, this was not a true head to head comparison, but likely enough information to tell them whether or not to proceed with the head to head.





I have pasted the main results from study 175 below (though you are welcome to go through the entire 158 Grassley letter). What you can see is that the higher dose of Actos dropped triglycerides about 16 points (or about 10%) and Avandia at the higher dose raised triglycerides by about 11 points. Study 175 also showed that Avandia raised the LDL or bad cholesterol by about 10%, where Actos didn't have any change (advantage Actos) and that Avandia raised HDL or good cholesterol by about 4 points (roughly 10%), whereas Actos didn't really raise the HDL (advantage Avandia). Given that these results might put Avandia at a competitive disadvantage, GSK decided not to publish their findings and did not to go forward with the head to head study. Thus, the company did not secretly hide data that Avandia was dangerous (as Grassely and the Times suggest). Rather, GSK chose to not to publish an Actos study that didn't make Avandia look any better.

Now you might argue (am I am guessing that this is Grassley's point) that since Actos did better with triglycerides and LDL cholesterol than Avandia, that this shows Avandia might pose a cardiac risk. In fact, many have argued this as the very reason that Avandia seems to show safety signals in meta-analyses and Actos doesn't. However, time and time again, surrogate markers have shown us that they don't translated into outcomes. First, all diabetics should be on statins, so these minimal changes in lipids seen by both TZD's probably don't matter clinically. Second, both the FIELD trial and the recently published lipid arm of the ACCORD study showed that even if you treat diabetic patients with medicines that truly lower triglycerides (fenofibrate), it doesn't reduce heart attacks. Furthermore, though there are only a few studies in diabetics showing raising the HDL decreases heart attacks, even Dr. Steve Nissen in his PERISCOPE trial that showed Actos to reduce plaque build up compared to the older sulfonylurea drug, suggests this may have been due to the HDL effect. In other words, if HDL is more important in preventing heart attacks in diabetics than triglycerides, maybe Avandia is the real winner of study 175. Though I am not going to suggest (similar to the Times and Grassley) that study 175 showed Actos to be more dangerous to the heart due to Avandia's HDL benefit, it is clear that study 175 does not show in any way, shape or form, that Avandia is more dangerous than Actos.


However, if you still feel the public has a right to know all the data (which is a valid point), GSK didn't just "hide" the data; they had an obligation NOT to publish it. GSK (and every drug company) is a for profit business. Though they have an obligation to patients to make safe and effective products, they also have a fiduciary obligation to their shareholders to make money. Similarly, though Toyota has an obligation to warn the public about any safety issue with its cars, it can not publicly declare that their Sienna minivan has fewer cup holders than Honda's Odyssey mini-van. Nor should Starbuck's need to announce that in a blinded taste test, most people preferred the cheaper McDonald's coffee. In all three cases, share holders could sue the company.


The main problem is that the majority of pharmaceutical studies are done by the pharmaceutical companies. The purpose of these studies are to get their drug approved for initially for availability on the market and eventually use in other indications. In 2005, pharma spent nearly $40 billion in research. This dwarfed the entire NIH budget that year of $28 billion dollars, and the NIH does very little research on drug therapies. You can't have your cake and eat it to. If you want unbiased studies, and if you want science and not marketing to determine what studies get done, then someone besides the industry is going to have to do the work.

Indeed, it is rare that industry published head to head studies. In some cases, such as Merk's ENHANCE study which showed its expensive product Vytorin to be no better a reducing plaque buildup thant its recently generic simvastatin, the company lost big time. Use of Vytorin decreased dramatically, and Merk's stock plummeted. In fact, the TIDE study comparing Actos to Avandia (which the FDA advisory committee approved to go foward with 19 to 10), only got started in the first place because the FDA mandated that GSK do this study. Ironically, in this Avandia "win" from this past week, GSK is footing the bill for TIDE, spending millions while sales of Avandia will likely plummet. If we had comparative effectiveness research in place back in the 90's the TIDE study would likely have already been completed and we would know with 100% certainty whether there was any TZD risk for heart attacks and any difference between Actos and Avandia.


This is why comparative effectiveness research is so important, and why it is a much needed improvement that came out of the recently passed health care reform bill. The health care reform act included about $500 million for a Patient-Centered Outcomes Research Institute
to do comparative effectiveness research. The funding builds on about a $1 billion dedicated to comparative effective research from the stimulus package. However, though an important start, $1.5 billion over the next decade is a drop in the bucket compared to the funding needed to answer important clinical questions about which medications are best in which patients. One possibility would be to have industry and government partner in such a way that the industry kicked in with only limited input into the research, which would also absolve them from their fiduciary responsibility to their shareholders. Other agreements could include more data transparency and independent analysis of drug company sponsored studies before publication.

The recent Avandia hearing with its media sensationalism from the Times and politicking by folks like Grassley and insiders within the FDA shows that when science, politics and media mix; patients lose. Not only is more transparency needed in both the FDA and the industry, but we have not been wise to allow industry to foot the bill for most of our research on therapeutics. Comparative effectiveness research provided in the health care reform bill is a start, but is grossly underfunded for what is really needed.

One Patient Stays on Avandia, One Patient Switches to Actos

The calls/emails have already started to come in, and I expect more, as I have a lot of diabetes patients and have been an avid user of the TZD class. There are many reasons to like the TZD's:
1. The older, generic medicines like metformin and sulfonylureas are known to fail over time. After 3 years, most patients on one of these drugs lose control of their blood sugar. In contrast, patients on TZD's maintain glycemic control (at least up to 4-5 years which was shown in the ADOPT study).
2. The TZD's don't cause hypoglycemia, which is a really bad side effect of insulin and the sulfonylureas.
3. Many diabetic patients need more than one drug, so even if you start with metformin, you are going to have to choose between a TZD (well studied, no hypoglycemia), a sulfonylurea (well studied, causes hypoglycemia), or a DDP4 inbitor like Januvia/Ongyza (not as well studied, no hypoglycemia).
4. TZD's have other benefits that the other diabetes drugs don't, such as improving good cholesterol or HDL, and decreasing triglycerides or fats. In his presentation the Periscope study, which showed Actos prevented plaque build up, Dr. Nissen (wonder why he likes Actos?) compared these results to other similar cholesterol lowering studies and showed an ldl-independent effect of the TZD's in their ability to prevent plaque build up. He believed this was due primarily to increases in HDL.
5. Using a TZD, likely because of sustained glycemic control, prevents the need for insulin. This was shown in the recently maligned RECORD study and the NIH sponsored BARI-2D study. Insulin causes hypoglycemia and most of my patients would like to avoid insulin.

The first patient contacted me by email related what he had heard about the FDA panels finding. He understood that they recommended not to pull the drug, but also felt that there were enough concerns that he wanted to switch. He was on Avandia 4mg, so I switched him to Actos 45mg.

It is important to note that the TZD's have their maximal effect at the maximum dose. Though the maximum dose causes the most side effects, I have found that if used early in the course of disease, side effects are minimal. The most common side effect of the TZD's is edema, or fluid retention. Use of a low dose fluid pill (which many diabetics use anyway in order to keep their blood pressure controlled) seems to eliminate this problem. For metformin, the best dose is 2000mg a day (usually 1000mg twice a day).

This brings me to the second patient who called me with similar concerns. He had been taking Avandamet 4/1000mg twice a day for about 7 - 8 years with outstanding diabetes control. In discussing the switch to Actos, we uncovered a problem. The equivalent dose of Actos is 45mg. Like Avandia, Actos comes in combination with metformin, called Actoplusmet. Actoplusmet comes in 15/500mg and 15/850 and is to be taken twice a day. If you do the math, it is very hard to get the 45/2000mg a day that would be equivalent to the Avandamet dose that has kept this patient under control for so long. We could do two pills in the morning and one a night (a more complicated regimen), but would be over (more side effects) or under (less efficacy) on the metformin dose between the 850 and 500 versions. Actoplusmet was just approved as an extended release product. This can be taken once a day (easier regimen). Actoplusmet XR comes in 15/1000 and 30/1000. If we went this route we could have the patient take one of each. The problem is that his insurance company will consider this two different medications and charge him two separate co-pays. He could take the 30/1000 and use one and a half tablets a day (wouldn't cost him more), but we would be short on the metformin, and it is generally not a good idea to split extended release pills. After spending 10 minutes discussing the above dilemma, he decided that it was simply too complicated to switch and he would stick with the Avandamet, unless the FDA decided to pull it.

Actos and Avandia are both good medications. Many of the FDA panelists who voted to pull Avandia or severely restrict it, mentioned that they did so because Actos was available and they saw no clear avantage of Avandia over Actos. No one mentioned the dosing. This is likely because few on the panel actually treat patients with diabetes. The only panelist really pushing for options was the patient advocate.

In addition, there is really no compelling evidence to believe that Actos is any safer than Avandia. The AHRQ (government, non-pharma) commissioned a study to look at this, and they found no difference. A Science Advisory From the American Heart Association and American College of Cardiology Foundation also looked at this issue (most of the authors had no ties to either product) and similarly found no substantial difference between Actos and Avandia with regards to safety. This is also why the panel voted 19-10 to move forward with the TIDE study.

Though, I am sure I will continue to get emails and phone calls from worried patients, many of the patients I have on Avandia take Avandamet 4/1000mg twice a day. Hopefully, they will read my blog before calling as multiple 10 minute phone calls start to add up.

FDA Panel Recommends Keeping Avandia on the Market

As I mentioned in my post Avandia Smackdown!! , I suspected that Avandia would likely stay on the market. The story is all over the headlines, including the Wall Street Journal's FDA Panel Backs Keeping Avandia on the Market. The 12 panel members wanted to pull Avandia, but 20 said it should stay on the market. More interestingly, though the majority of the members felt there were signals of risk, the vote was 20 to 10 to proceed with the controversial TIDE trial, which Drs. Graham and Sen. Grassley said were unethical.

I have been following the hearing closely for the past few days via Twitter and live video feeds from CNN. Here are some initial thoughts.

1. Despite the panel's concerns about Avandia safety, the clear majority felt that there was simply not enough data. Many were concerned that studies like Nissen's meta-analysis were just not strong enough. Though they favored long term, randomized trials to definitely answer these questions, unfortunately, there were enough concerns about the RECORD study by some (low events, withdrawals, and some missing data) to be convincingly reassured.
2. The sentiment of many was because Actos didn't show as strong signals, it remained a better option. Many who chose to pull Avandia stated for the RECORD that Actos' availability was a deciding factor. This is concerning because the data for Actos safety is extremely weak (not that I think Actos is dangerous). One panelist stated what I have heard before, that "the absence of evidence does not equal the evidence of absence."
3. Many panelist stated that they were putting on their "public health" hats, meaning that even though scientifically they were not convinced of real harm, because there was a possibility of harm, they voted to remove or proceed with caution. This is VERY important, because as a clinician (which many on the panel were not), you have to balance risk and benefit every day. Is the side effects of a particular medicine worth the benefits of the medicine? Is the potential harm of radiation worth the need for a CT scan? I think if more practicing doctors were on the panel, fewer would have voted to remove the drug.

What now?
Ultimately, the FDA will decide what to do. Since the FDA doesn't have to agree with the panel and especially since the panel seemed split, the FDA could decide to remove Avandia anyway or keep on the market with certain restrictions. Given that 10 voted to have very strict warnings, it is likely that's what the FDA will do. These stricter warnings will likely include something like requiring only a diabetes specialist, i.e. an endocrinologist be able to write a prescription for Avandia. This language will be crucial, because even if Avandia stays on the market, if the restrictions are tough enough, no doctor will ever write for the prescriptions.

Despite all the holes that Avandia's opponents poked in the data, I remained convinved that the preponderance of the data points in Avandia's favor. It doesn't appear to cause increased heart attacks, it certainly doesn't cause increased death, seems to decrease stroke, and clearly decreases the use of insulin. I will continue to write for the product unless it is pulled from the market, newer restrictions make it virtually impossible to prescribe, or my patients request being placed on a different medicine.

Avandia Smackdown!!

This is it. The final countdown.
The fate of Avandia will likely be decided in a matter of days.
The outcome will likely have long lasting impact regarding how the FDA manages potential safety issues with any current or future drugs on the market.
That is because on July 13th and July 14th, the FDA will hold an advisory committee to review the safety data on GSK's drug Avandia.
I have blogged on the Avandia topic extensively. (In particular see Avandia Vindicated and Diabetes Conspiracy).
Below is a re-cap of all the major events in the saga as well as possible outcomes and my prediction as to what will happen.


Prelude- Vioxx (2001 -2004)
It is important to note that the Avandia story begins with Vioxx. Prior to Vioxx, many doctors prescribed heavily marketed drugs with less concerns about safety, thinking that if a drug had been approved by the FDA, they were likely safe. One of the major studies that led to fall of Vioxx was published in JAMA on August 22nd, 2001 by Cleveland Clinic cardiologist Dr. Steve Nissen. It took nearly three years until September 30th, 2oo4, when Vioxx was finally pulled from the market. Dr. David Graham, an FDA insider who works on drug safety was clearly frustrated by the FDA's apparent lack of concern. He was called to congress in November of 2004 to testify regarding what other drugs the public might be concerned about. Though Avandia wasn't named as one of Dr. Graham's five drugs to look out for, his testimony to congress against his own institution made it clear that Graham intended to be a whistle blower and would place the FDA safety folks at odds with the other branches of the agency


August, 2006- FDA becomes aware of potential Avandia issue
In August of 2006, GSK submitted both a pooled analysis (meta-analysis) of 42 separate double-blinded, randomized, controlled clinical trials to assess the efficacy of rosiglitazone (Avandia) for treatment of type 2 diabetes, which surprisingly showed a potential increase in myocardial ischemia in patients taking Avandia compared to placebo. There were no problems when Avandia was compared to other diabetes meds, no issues with death, heart attack, or other adverse events in the FDA's meta-analysis. These results were surprising because though Avandia was known to cause fluid retention and a possible risk of congestive heart failure (CHF), due to some of Avandia's other properties (lowering triglycerides, increasing HDL, decreasing CRP), if anything, Avandia should have prevented heart attacks.

Rather than create a public hysteria and mass panic, the FDA decided to take a wait and see approach for several reasons. First, the FDA knew that two large, randomized trials (ADOPT and DREAM) were about to be published that could help shed some light on this surprising and potential safety signal. In addition, the RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. Though the results would not be available until 2009, the study had be going on for almost 2 years and an independent group which periodically looks at the study to assess safety (commonly done in safety studies) had not reported any problems. And in fact, both DREAM trial and the ADOPT trial not only showed that Avandia prevented diabetes and sustained glycemic control better than the other available diabetes agents respectively, there were NO signs of heart attack.

Thus, the FDA felt confident in their decision not to needlessly scare the public, but rather wait until about June, 2009 when the RECORD trial was likely to report out. Given that it was a large, randomized trial specifically designed to look at Avandia and cardiovascular safety, the RECORD study would be able to definitely answer the question once and for all.


May 2007- Nissen Meta-Analysis published.
Due to a previous settlement regarding their drug Paxil by then attorney general Elliot Spitzer, all GSK's clinical trial data was publicly available. Dr. Steve Nissen was therefore able to perform his own meta-analysis of the GSK studies. Given that there had been no public mention of Avandia heart attack concerns, I suspect someone inside the FDA tipped off Dr. Nissen. His controversial and often criticized findings of a 43% increase in heart attacks with Avandia were rushed to press and published in the New England Journal of Medicine. The news created a media frenzy. Congressional hearings were called for by Senator Charles Grassley the very next day (almost as if Sen. Grassley knew about the results before they were published). In the following week's issue of the New England Journal, the interim results of RECORD were published ahead of schedule, mainly due to concerns that the RECORD study itself could be jeopardized as patients might pull out of the study if Avandia were dangerous. Though only more than half way done, the study seemed to show no signs of heart attacks, thus refuting the Nissen publication. However, the study was accompanied by not one, but three editorials discrediting the study, and the controversy persisted.

July 2007- First FDA Advisory Committee Convened
Given the publicity of the Nissen study, the FDA met to discuss the safety of rosiglitazone. After review of all of the FDA's (not Nissen's) data, they saw something that didn't make sense. Their own meta-analysis showed a signal of myocardial ischemia, but analysis of the ADOPT, DREAM and RECORD trials, as well as analysis of large claims databases showed nothing. The FDA voted almost unanimously to keep Avandia on the market. However, they added a boxed warning to Avandia. This boxed warning remains one of the most confusing warnings I have ever seen, stating that there is contradictory evidence so no conclusion can be made. Nevertheless, physicians who may have been on the fence about prescribing the drug, likely stopped writing prescriptions for Avandia. The class of medications, called the TZD's, decreased in general use, and Actos, the competing TZD which had 50% of the market share of TZD prescriptions became the heavily favored product.

June 2009- RECORD study results published
During the ADA's annual meeting, the long awaited study results of the RECORD trial were finally published. The study that should have put the issue to rest showed absolutely no difference in cardiovascular issues with Avandia. In addition, patients who used Avandia had improved diabetes control and less use of insulin. At the previous years ADA meeting, two other randomized studies (ACCORD and VADT), which both used Avandia extensively also showed no issues related to Avandia. Given RECORD, ACCORD, ADOPT, DREAM and VADT there have been randomized, controlled trials of 26,000 patients that have been studied over 4 to 5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks. Yet, critics (mainly Nissen and Graham), still had their doubts. The FDA decided that they would meet in July 2010 to review all the newest data and re-look at the controversial issue of Avandia.



February 2010- Grassley releases investigation of FDA and GSK
As above, Sen. Grassley called for an investigation back in 2007, and it took three years to finally release his findings. The report is an indictment of both the FDA for not taking Avandia risk seriously and GSK for hiding data from the public. Interestingly, the report fails to mention any of the studies published since May, 2007 showing Avandia to be safe. It as if time stood still in the Grassley report. The other issue that the Grassely report raises is the ethics of the TIDE study. The TIDE study, which the FDA requested GSK perform is a head to head study comparing Actos and Avandia in regards to safety. Grassely contends that since Avandia risks are known, the TIDE study is unethical and should not be performed.



June 2010- Nissen and Graham take one more shot
In conjunction with the June ADA meeting and weeks before the July FDA advisory committee, both Dr. Nissen and Dr. Graham have separate publications once again questioning Avandia's safety. (Both claim publicly that the timing of the release of this data is coincidental). The Nissen study is an update of his 2007 study, which both addresses some previous criticism of the original study and adds new data, including the RECORD study. Since this is virtually the same study as he did in 2007, it is not surprising that his findings are the same. The Graham study analyzed Medicare claims databases comparing Actos and Avandia. Graham claimed that Avandia was far riskier than Actos when looking at stroke, heart failure and death. Retrospective reviews of databases are legitimate forms of research, but have even more limitations than meta-analaysis. More interesting (which no media seems to be reporting on) is that Graham's study showed no difference between Avandia and Actos when it came to heart attacks. Stroke had never been a question, and even Nissen's analysis showed Avandia didn't increase death; CHF is a risk for both with multiple studies suggesting the risk is similar. Nonetheless, both studies got major media attention, overshadowing a 3rd study presented at the ADA (analysis of BARI-2D) which showed Avandia prevented stroke, heart attacks and death!.


July 2010- FDA Advisory Commitee
The FDA will review all the data mentioned above and hopefully come up with some conclusion. The meeting was planned in advance of Sen. Grassley's report, and was timed such that RECORD, BARI-2D and Graham's review could be incorporated with existing data. Expect debate to be particularly heated.


What are the possible outcomes?

Avandia Gets Pulled from the Market ( Odds 30-1)

This would also be the end of the TIDE study. This is a relatively unlikely scenario given that, with the exception of Graham's retrospective reivew, the only new data since 2007 are RECORD and BARI-2D, which are large, randomized prospective trials specifically designed to look at cardiovascular safety, both showing no issues with Avandia. Another intersting aspect, (which I blogged about in Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III) is that because of the Avandia scare, the FDA developed new criteria requiring that ANY new diabetes drug that gets approved by the FDA must first show that it does not cause heart attacks. Specifically, the FDA now requires randomized clinical trials that show a drug does not cause heart attacks with the upper limit of confidence of 1.3. In other words, there needs to be 95% certainty that a diabetes drug couldn't possibly increase the risk of heart attacks by as much as 30%. The confidence intervals for the RECORD trial for heart attack fall under 1.3. Thus, Avandia has already fulfilled the FDA's own criteria of being a safe drug in regards to heart attack. How could they possibly pull it?

That said, removal of Avandia is not impossible. Folks like Graham, Nissen and Grassely have a lot at stake in this game. Avandia staying on the market might make them look pretty bad. Rest assured that they will not go down without a fight.


Avandia is exhonorated (10-1)

Given the results of RECORD and BARI-2D, along with analysis of the VADT and ACCORD trials and multiple data bases, the FDA could be so overwhelmed with Avandia safety data that it proclaims Avandia to have no risk of heart attack and pulls any mention of this from its label. However, with all the surrounding controversy, this seems a little unlikely. The FDA has been harshly criticized for being soft on safety. That said, the FDA might want to take a stand against outsiders (Nissen, Grassley) as well as insiders (Graham) trying to do their job for them.

Nothing Happens (1-1)

This is the most likley scenario. There are no clear winners or losers, so everyone can save face. In this scenario, the TIDE study would likely proceed as planned, but not necessarily. The problem with this scenario is that it leaves physicians and patients in the dark. Is Avandia safe or not? The FDA owes the public an actual opinion, unlike its stance in 2007, which essentially was "we dont' know." In this scenario, the devil is in the details. The FDA will have to update Avandia's label with regards to the cardiovascular safety . The label could be harsher towards Avandia (i.e. more studies suggest concern), reassuring (i.e. despite one meta-analysis a multitude of randomized trials show safety) or neutral.


Actos vs. Avandia?

Finally, I have been asked multiple time about Actos vs. Avandia regarding safety. The conventional wisdom is as follows: even if there probably isn't any cardiovascular risk with Avandia, why would you not just simply switch to Actos just in case? Why do we even have Avandia on the market if Actos exists?

I use both Acots and Avandia, and do believe there is a role for Avandia. There are two important things to consider with regards to this issue:

1. The absence of evidence does not equal the evidence of absence.
In other words, just because no concerns have been raised with Actos does not make it necessarily a safer choice. The vast majority of large, randomized clinical trials (the gold standard of science) have been done with Avandia and not Actos. Avandia beats Actos in trials almost 2:1. It would be like saying 5/10 studies show drinking Coke causes obesity in teens, but 0/5 studies show that drinking Pepsi does not cause obesity; therefore, we should have all teens drink Pepsi instead of Coke to avoid obesity. Some have argued that the reason there has been no signal seen in Actos is because of differences regarding each drug's affect on lipids, with Actos having slightly more benefit than Avandia. However, there has been no true head to head trial of both (which is why the TIDE trial would be scientifically beneficial), and the lipid data varies from study to study (cholesterol actually increased in Actos' one large, randomized trial called Proactive). Furthermore, since there are many more large, randomized trials with Avandia, none of which show an increased cardiovascular risk, one could make the argument that Avandia is the "safer" choice. I am not suggesting that Actos is dangerous. However, stating that Actos is a safer choice is not scientifically valid. The American Heart Association and the American College of Cardiology came to similar conclusions, stating no safety difference between the two products in their recent review of all the data (which was released ahead of schedule in response to the scathing Grassley report).

2. In my experience, the most effective dose of metformin is 1000mg twice daily. The most effective dose of each TZD is the maximum dose. If used early in the disease process, the typical side effects (edema) have been minimal, even at the maximum dose of each TZD. Thus, in my opinion, the perfect dose of Avandamet ( a product which combines Avandia and metformin) is 4/1000mg twice daily and the perfect dose of ActoPlusMet would be 22.5/1000mg. Avandamet is available in this does, ActoPlusMet is not. To give this dose of ActoPlusMet, patients would need two separate prescriptions, two separate pills, and two separate co-pays.

Addendum 7/9/2010
The FDA just posted the preliminary documents for next week's Avandia "smackdown."
A few tidbits:


1. I mentioned three possibilities for Avandia's fate: removal, label revision or no change. There is actually a little more subtlety regarding the label change. They might either remove altogether any mention of heart attack, add more warnings (such as recommending Avandia only be used if other meds fail), or add more warning AND restrictions to prescribing. See the FDA's exact wording below:

A. Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic CV events, or
B. Allow continued marketing and make no changes to the current label, or
C. Allow continued marketing and revise the current label to add additional warnings (e.g., contraindications for certain patient populations, recommendation for second-line use in patients intolerant of or uncontrolled on other anti-diabetic agents); or
D. Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use (such as restricting prescribing to certain physicians or requiring special physician and patient education)
E. Withdrawal from the U.S. market.


2. One of the presentations regarding the TIDE study, talks about the importance of large randomized controlled trials, citing all the bad things we would still be doing without the data. I love this....

If modern medicine relied on epidemiologic data, administrative databases, & meta-analyses of small trials to identify effective therapies, we would be …
routinely using HRT (WHI)
suppressing VPBs post-MI (CAST)
doing internal carotid artery bypasses (EC-IC study)
using alpha blockers to prevent stroke (ALLHAT)
giving estrogen to men with CAD (CDP)
giving high-dose GIK infusions in the CCU (CREATE)
using perioperative beta blockers (POISE)

2. There is going to be considerable time spent on poking holes in the RECORD study, which is really the pivotal evidence for Avandia safety. One of the main criticisms of RECORD is that the expected number of events (which determines how many patients they need in a study) was much lower than expected. Some has therefore stated that RECORD was "underpowered" to show Avandia is safe. In fact, the AHA/ACC consensus statement hinges its findings on this. However, the study was indeed powered to show Avandia is safe. The FDA presentation looking at this issue confirms this stating "Despite the initial over-estimate of events, the trial had substantial power to achieve its specified goal." This bodes well for Avandia.

3. Dr. Unger, a cardiologist from the FDA states that "the results of RECORD do not substantiate the findings from the Nissen/Wolski meta-analysis on myocardial infarction and cardiovascular death." In other words, from a cardiologist's perspective, RECORD proved Nissen wrong.

4. Nissen is not going down without a fight. Nissen main tactics seem to be 1) poke holes in the RECORD study and 2) present Actos (using non-head to head comparisons, meta-analyses, and claims databases) as a much safer alternative. Again, note that Takeda (makers of Actos) fund his research.

Boston Doctors Getting Paid to Switch Patients to Generics

Interesting video from WCVB in Boston about doctors getting kick backs from the insurance company to switch patients from branded medications to generic medications. New Rules To Protect Prescription Drug Customers

If people were concerned about undue influence when drug companies used to give physicians pens and other novelties (now currently banned by most companies), they should really be concerned about actually monetary payments. The patient interviewed in the Boston piece stated his doctor wanted to switch him from Lipitor to generic simvastatin (cholesterol lowering medications) but did not mention that he was being payed by his insurance company to do so.

Though this is the first case I have heard of doctors being incentivized to switch patients to generics, it happens in pharmacies all the time. What is horrible is that some pharmacies may switch patients to alternative medications even if that switch costs the patient more money. The example I am familiar with is albuterol inhalers (see FDA Announces End for CFC-Propelled Inhalers).

Switching to generics is itself not a bad things. I have blogged before that, for most medicines, generics are just as good as brand name medicines. For example, if the patient were on Zocor, a switch to the generic simvastatin would probably make a lot of sense, since the medications are basically equivalent and it would likely save the patient some money. However, in some cases, the small differences may actually make a difference. Back in November, I discussed this in more detail (see Generic and Therapeutic Substitutions ).

In this particular case, the therapeutic switch from Lipitor to simvastatin might have been devastating since Lipitor is a much stronger medication. The piece does not say what dose the patient was on, but if the patient required Lipitor 40mg or 80mg, no dose of simvastatin would have given him the cholesterol lowering he needed.

What should you do?
1. If you are on a branded medication, ask your doctor if there is a generic equivalent of the exact same medicine, or one that works just as well.
2. If you are on a branded medicine and asked to switch to a generic by your doctor, find out why he or she wants to switch.
3. If you are on a branded medicine and asked to switch to a generic by your pharmacy, find out why they want you to switch. Is your insurance company asking for the switch? Is the medicine the same (generic substitution) or slightly different (therapeutic substitution)? Regardless, make sure that you check with your doctor before switching any medicine.

Watch Your Step When Changing Asthma Medications

Back in February, I blogged about the FDA's recommendations regarding long acting beta agonist (LABA) safety (see FDA Blows it on LABA Safety ). A few weeks ago the FDA finalized these recommendations. Though some make sense, such as not taking a LABA without an inhaled corticosteroid (ICS), the main one I have a problem with is the following recommendation for patients controlled on an ICS/LABA combo like Advair or Symbicort:

"Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid."

Though the language is a little better than the original version which stated that "LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved," The notion that stepping down the LABA is preferred to stepping down the dose of the ICS is not evidence based.

As mentioned previously, all the controversy come from the SMART study published back in 2006 which looked at the safety of salmeterol. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including asthma death. However, the data from the SMART study was very clear that most of the problems came from asthmatics taking LABA's alone. More importantly, there were no increased problems (regardless of ethnicity) when using a LABA with and ICS. The ICS seems to protect against rare, but serious problems associated with LABAs. In fact, no one taking Advair or Symbicort equivalents in the SMART study died.

The FDA, acknowledging that some patients need ICS/LABA's to control their asthma, but concerned about any potential LABA safety issue, recommend step down care for those on combination therapy that are now controlled. Interestingly, the NIH guidelines when discussing step down therapy not only mention that it should be done carefully, as it might risk worsening asthma, but also focus on reducing the dose of the ICS, and not discontinuing the LABA.

The fact the FDA (whose job it should be to tell whether or not a drug is safe or effective) has clinical recommendations that seem to contradict the NIH (whose job it is to make clinical recommendations) is enough to cause concern. However, even more startling is that fact that the data shows that the FDA is clearly wrong. As mentioned in my previous post,
one study in the US of 647 patients controlled on Advair did worse when stepped down to ICS alone, and another French study of 467 asthmatics studied over 6 months showed that stepping down to a lower dose of Advair was fine, but stepping down to ICS alone (what the FDA recommends) caused problems. Today, a new study was just published confirming the same thing: stepping down the LABA is ill advised in a well controlled asthmatic. The study, published ahead of print online, looked at two large managed care databases over several years. They found 4350 asthmatics who stepped down from Advair: 3881 stepped down to a lower dose of Advair and 469 stepped down to the ICS alone (what the FDA recommends). When they matched the patients for age, demographics, etc. they found that the asthmatics stepping down to the lower dose of Advair had 30% fewer prescriptions for short-acting beta-agonists, a 26% lower risk of receiving systemic corticosteroids, and a 48% lower risk of asthma-related hospitalization or Emergency Department visit during follow-up.

Don't take my word for it
If you still remain skeptical, don't take my word for it. Look elsewhere. In Canada, where they have access to the exact same data, the label for Advair is completely different. You can access the full label by clicking here. However, the following excerpt says it all:

"Patients should be regularly reassessed so that the strength of ADVAIR® they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose of fluticasone propionate at which effective control of symptoms is maintained."

In other words, the Canadian Advair label is consistent with what the evidence shows, and consistent with what our own NIH guidelines recommend. The FDA's versions is the opposite.
In the UK, the safety information not only has no mention of stepping down, but their is also no "black box" warning or even mention of the SMART study. The Brits only mention SMART when discussing Severent.


Bottom Line: The LABA safety issue is more about politics then science. LABA's should not be taken alone, but in combination with and ICS (like Advair and Symbicort) are the most effective agents for asthma and are completely safe. The goal for any physician is to have the patient on the lowest amount of medication possible to keep their condition under control. For asthmatics well controlled on ICS/LABA, the data is crystal clear. Despite what the FDA says, it is better to go to a lower dose ICS and remain on an ICS/LABA combo, then to go off the LABA and remain on the ICS alone.

Should You Friend Your Doctor??

My friend and colleague Katherine Chretien has a provocative Op-Ed in USA Today entitled A doctor's request: Please don't 'friend' me which asks the question whether doctors and patients should interact in social networking sites such as Facebook. Social networking has huge potential in health care regarding the sharing of information and ideas, and could possibly even enhance communication between doctors and patients. However, as Dr. Chretien points out, many physicians have steered clear of social networking sites, and those who do, "actively dread having a patient add them as a friend." The main problems with social networking and patient-physician interactions boils down to confidentiality/security and boundaries.

Confidentiality/security is less murky issue to deal with, and is applicable to all online communications between doctors and patients. First, there has to be privacy. If a patient wants to post their entire medical history to the world, they have every right to do this, but doctors have to ethically and legally maintain a patient's privacy. This should not be too difficult, but could get tricky in a social networking world. If a patient posts "Not feeling well today," a reply from their physician "don't forget to take your meds," would likely be a violation of privacy and confidentiality. In addition, all online communication must be secure. Regular email does not even meet that requirement. In fact, unlike email, both parties need to be logged in to Facebook to send and receive messages, making Facebook a better choice for direct communication between doctors and patient then regular email. Part of security also means encryption. According to Facebook they "always posts to a secure page when users are logging in and employs industry standard encryption."

The bigger problem has to do with boundaries. The doctor and patient relationship is unique in that is should be close and personal, but if too close, the doctor's objectivity could be compromised. This is why it is considered unwise (and sometimes unethical) for physicians to treat their relatives. According to Dr. Chretien, "the thought of opening up our personal pages filled with family photos, off-the-cuff remarks and potentially, relationship status and political and/or religious views to our patients gives us the heebie-jeebies." However, is having family photos online any different than having family photos in one's office? Does an off the cuff remark revealing a physician's political slant any different in the office than on the web? Physicians are often known to personalize their office space with items of personal importance and significance. Family photos, an artifact from a vacation, a golfing trophy, a treasured gift from a patient, etc. I believe this is a good thing. It humanizes physicians and hopefully assists patients in making connections with us.

The two problems with Facebook are controlling one's own privacy and the use of the word "friend." Facebook was founded by Mark Zuckerberg with his college roommates and fellow computer science students. In other words, it was invented by kids. The term used to link one another is "friend." However, this is not "friend" the noun which we are all familiar with, but rather "friend" the verb. Though "friend" the verb can theoretically used to mean "befriend," in conjunction with Facebook it is the mechanism by which one connects with another individual online. The confusion is not unique to the doctor-patient relationship. I am sure many young adults wonder what to do when a parent "friends" them. If instead of "friend", Zuckerberg and colleagues had used the word "connect', we would probably be less concerned about boundary issues. Is it wrong for a physician to "connect" with patients online?



The issue of controlling one's own privacy is likely what truly concerns many physicians when considering using social networking platforms like Facebook with patients. After all, the physician who personalizes his or her office space has carefully decided what he or she wants patients to know about them. Even if a physician is careful in posting information on Facebook knowing that patient-"friends" might see, other non-patient "friends" can tag the physician in a compromising photo or leave an inappropriate reply that could be easily viewed by the patient. This is obviously a barrier, but this barrier is easily overcome. The easiest way to avoid this problem is to have two separate Facebook accounts: a professional/patient account and a private/personal account. A variant of this would be setting up a "Fan" page. (Please feel free to click on the blue box with the "F" to the right to become a "fan" of Dr. Mintz). Finally, any Facebook user should be familiar with the privacy settings on Facebook. These can be customized. For example, you might create a groups called "patients", "relatives" and "close personal friends"; assigning different permissions to each of these groups.

As the Op-Ed points out, there are currently no national guidelines for social media use by physicians and, as mentioned above, confidentiality and boundary issues are difficult and controlling one's own privacy may not be easy for many physicians. However, most of the barriers for using social networking between doctors and patients can be overcome. Given that, and the potential uses and benefits social networking can provide, I would somewhat disagree with my friend (correct usage of the noun) that physicians shouldn't be "friends" on Facebook with patients. However, if they do, they should proceed with extreme caution.

Fracture Risk and Acid Blocking Medications: What Should You Do?

Yesterday, the FDA released a Drug Safety Communication warning about a possible risk of increased fractures with acid blocking medications called proton pump inhibitors or PPI's.

PPI's have been a major advance in medical science. Prior to these and ealier medications, the treatment for severe gastroesophageal reflux disease (GERD) was major surgery. PPI's are now commonly prescribed for GERD and less serious heart burn, many are generic, and some are now sold over the counter. The popular PPI's include Nexium (esomeprazole), Prilosec (omeprazole), Prevacid (lansoprazole), and Protonix (pantoprazole) which are available by prescription. Prilosec OTC and Prevacid 24HR are sold over-the-counter (OTC). Given the use and popularity of these medications, this warning may cause great concern among patients who rely on these medications.

What did the FDA find?
The FDA analyzed the data from several epidemiologic studies in thousands of patients studied for several years and in 6/7 studies found a greater risk for certain kinds of fractures when patients took PPI's. These risks seemed to be the greatest when patients were taking the medications regularly, for a long time, and at a high dose.

So is this a real problem?
Maybe. It is important to know that the gold standard of studies is the randomized clinical trial (RCT). Only RCT's can prove a cause and effect. None of the RCT's with PPI's thus far have shown and increase fracture risk with PPI's. The problem with RCT's is that they are hard to do and are usually limited in time (6 months) and have fewer patients. So a rare but serious side effect is unlikely to be picked up in an RCT. The epidemiologic studies are useful, but have limitations (which the FDA readily points out). These studies are case-control, meaning they look for people who had fractures, find similar people who didn't have fractures, and then see how common PPI use was in each group. Though the studies show that people with fractures were more likely to take PPI's than people without fractures, this doesn't mean that PPI's cause fractures. Maybe the folks who took PPI's had stomach troubles and were less likely to take things that prevent fractures like Calcium or Bisphosphates (drugs which prevent fractures but are relatively contraindicated in those patients with GERD). In addition, these studies use claims databases. This means that to get the data, doctors never examined or interviewed patients, rather the investigators looked at insurance claims for fractures, medication use, etc. For example, we don't know what the bone density scores (DEXA) were for the patients in this study. It is very possible (and even likely) that the patients in the fracture group had lower DEXA scores, and this more than the PPI use accounted for fracture. Also, if you have ever received a bill or claim notification from your insurance company, you problem know that the information they contain is not always 100% accurate. That said, the number of patients studied and the consistency of this relationship suggests that there may indeed be a cause and effect.

What should you do?
It is unlikely that short term use of PPI's substantially increase risk of fractures. So if you need an occasional Prilosec OTC (like after a big barbecue this Memorial Day weekend), this is probably fine. If you need to take PPI's, either prescription or over the counter, on a daily basis and have symptoms when you do not take them regularly, this could be a sign of more serious disease and should be investigated by a physician (regardless of a fracture risk). For those patients who have had an extensive medical work up for a stomach condition and told by a physician that taking a PPI on a daily basis for years to come is the recommended treatment, then they should discuss the risks and benefits of PPI's as it relates to fractures. This would be particularly important if you have an increased risk for fracture such as a previous fracture, family history of osteoporosis, or low bone density.

Lipitor or Crestor for LDL's above 160

I just read A systematic review and meta-analysis on the therapeutic equivalence of statins. This artilce will not make any major U.S. headlines because it is a Taiwanese study from a not very well known journal. However, the methodology is sound and makes an important point to patients who need a statin and are deciding between a generic and more expensive brand name medication.

The study did a systematic review of all the studies which compared the different statins. They found that at comparable doses, statins are therapeutically equivalent in reducing LDL (or bad cholesterol). This would suggest that if statins are essentially equal, provided you use the right dose, then you should always go with a generic. However, the other thing they found was that "the only two statins that could reduce LDL-C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher." In other words, those patients who need cholesterol lowering drugs and have to get their cholesterol down by less than 40% should be OK with generic, but those who need to get their LDL cholesterol by more than 40% should use either Crestor (rosuvastatin) or Lipitor (atorvastain). Though new guidelines should be out by the end of the year, current guidelines suggest that patients with increased risk for heart attack and stroke (all diabetics, mulitple risk factors,etc.), who are generally the patients we use statins in, need their LDL's under 100. This means that if you are at increased risk for heart attack and stroke, and your LDL is 160 or above, you should not take the generic (even if it is cheaper), but take the more expensive branded cholesterol medicines.
Fortunately, as I mentioned in a recent post Are Drug Reps and Free Samples Bad For Patients? It Depends, both companies offer coupons to offset the additional out of pocket costs, so you should not pay much more for Crestor or Lipitor than what you would pay for a generic medication.

Are Drug Reps and Free Samples Bad For Patients? It Depends

One of my favorite blogs, KevinMD, featured a post by Internist and fellow blogger Dr. Leslie Ramirez (founder of Leslie’s List, which helps the uninsured and underinsured find more affordable medications and health care services) on the true cost of free drug samples. Her point was that "free" drug samples may cost a patient in the long run if they are followed up with an expensive prescription that the patient can't afford. I posted a response on Kevin's site (more below) stating the issue was a little more complex, as Dr. Ramirez' example applied specifically to a patient who was paying out of pocket for medications, which is not usually the case. However, this post received numerous responses about the value/evils of both drug reps and the samples they provide. Below is an edited/expanded version of my replies.

The Benefit and Harm of Reps and Samples
Do drug reps/free samples…
-influence doctors? Absolutely.
-increase prescribing of non-generic meds? Absolutely.
-contribute to health care dollars spent on meds? Absolutely.
-harm or are bad for patients? It depends.

It is true that whenever a generic medication has equal safety and efficacy as a branded medication, the patient and public benefit when a generic is used. However, just because there are generic medications available, does not always mean that generics are the best choice for patients.

A good example is type 2 diabetes. The RECORD (see For the RECORD, Avandia does not cause heart attacks) study looked at cardiovascular safety of the much maligned drug Avandia. (RECORD showed it not to increase risk of CV death or hospitalization-something the media continues to ignore). The study took patients on a generic diabetes medication (either metformin or sulfonylurea) and randomized them to either an expensive, branded diabetes medicine (Avandia) or the other generic. Patients in the Avandia group who still had uncontrolled diabetes on Avandia + one generic could add the other generic. Patients in the other group who were uncontrolled on both generics had to go to insulin.


In addition to showing no difference in cardiovascular safety (primary endpoint), the patients in the Avandia group had better diabetes control, less weight gain, better cholesterol profiles, less hypoglycemia and less insulin use. In other words, though it certainly costs more money, (in this study) it was better to add Avandia then sticking with only generics. This should not be surprising since we know that the older diabetes drugs fail after a few years, and that TZD's like Avandia (seen now in ADOPT, RECORD, and BARI 2D) sustain glycemic control.



There are a few other examples where generic products exist, but branded products may be better. Branded statins (Crestor, Lipitor) are likely better then generics for patients with high cardiovascular risk who need to get their LDL (bad) cholesterol down more than 40%. In hypertension, losartan is the first generic angiotensin receptor blocker (ARB). Though there are several ACE inhibitors that are good once a day generics (lisinopril), up to 10% of patients will get a cough and need to be switched to an ARB. Now we finally have a generic ARB, except this one is not nearly as good as the other 4 branded products on the market. Because insurance companies will likely make it very difficult (higher co-pays and prior authorizations) to get one of the branded ARB's, patients will likely need to get a cough on an ACE and then fail losartan, before they are allowed to use the newer, better ARBs (and will still have a very high co-pay).



In addition, there are many medications that have no generics. All the respiratory medications (Advair, Symbicort, Spiriva, etc.) essentially have no generic equivalent. Having a drug rep provide samples of these meds will (as stated above) certainly increase prescriptions and therefore increase healthcare spending. However, asthma kills about 11 patients a day, COPD is the 4th leading cause of death, and both conditions are substantially under treated. Writing more prescriptions of these medications, and thus the reps that provide them, should therfore be a good thing. Even if the medicines are costly, their increased use will prevent exacerbations, hospitalizations, and even death (which have their own costs).



There is also the issue of direct cost to the patient (out of pocket costs) and the convenience factor. The FDA just approved a combination pill of Nexium and Naprosyn for rheumatoid arthritis. Many patients with rheumatoid arthritis need to take NSAIDs like naproxen on a regular basis. One of the side effects is stomach ulcers. Acid blocking proton pump inhibitors (PPI's) like Nexium can prevent these ulcers and guidelines recommend the use of PPI's with chronic NSAID therapy. The newly approved, branded pill will be an expensive, once a day pill that will treat the arthritis and protect the stomach. However, Prilosec (another PPI) and Naprosyn, are both over the counter. Why not just take two over the counter pills a day instead of an expensive branded pill? CVS brand naproxen would cost about 10 cents for two 22omg pills (prescription dose is 500mg), and one Prilosec 20mg OTC (not as strong as Nexium, but should do) is about 70 cents a day. Thus, a patient needing NSAIDs and stomach protection would need to take 3 pills at 80 cents/day, or $24/month. However, it is very likely that the drug company will provide coupons for patients that guarantee them that their co-pay is no more than $25/month. I would think that most patients would prefer the better, once a day pill than the 3 pills a day for about the same price. (There is also a potential safety benefit as combining the pills ensures the stomach is protected when taking an NSAID).

As already alluded to, the issue becomes further complicated when insurance coverage, samples and coupons create complex equations where decision making becomes a challenge. One example would be high cholesterol. Let’s say your bad cholesterol or LDL is 160 and your doctor tells you it needs to be under 100 based on your risk for heart attack and stroke. Simivastatin is generic and has been proven effective, but you will likely need the highest dose of 80mg to get to your goal (the higher the dose, the greater the likelihood of side effects). Generic simvastatin (no samples) costs you $10 month at your local CVS. There is also Lipitor, a branded drug that will get you to goal at a 20mg dose, but at a price of $25 per month. However, I can give you a four week sample of Lipitor to try (to make sure there are not side effects, etc.) and a coupon that will lower your monthly cost to $15. This will last for a year (at which point Lipitor should be generic). Using the branded product with samples and coupons, the additional out of pocket cost to the patient is only $50/year or an extra $4/month, but they get to try the med first, and received a drug that worked better, with fewer side effects. Which is better for the patient? (Before you say that $50/year is a lot for a poor person, keep in mind that very poor patients are on Medicaid and won't pay any difference for the medications, and people who do not have prescription coverage might have problems being able to afford either, as generic simvastatin 80mg is $33/month).


To be fair, there are PLENTY of examples where branded drugs are promoted heavily by the industry using drug reps and samples, where an equally safe and effective medications are available generically. Dr. Ramirez' post regarding generic citalopram and Lexapro is a great example. In addition, the argument can be made that drug companies should be putting their resources coming up with useful new agents, rather than re-packaging older medicines into one pill (like Naprosyn and Nexium).


The point is that the issue of the samples, drug reps and the industry is a complex one. The drug industry is one of the most profitable industries in the US. Their use of expensive, direct to consumer advertising may seem inappropriate to some, when so many in our country can not afford medications. Past excesses of lavish gifts to physicians (no longer allowed) and more recent settlements of off label promotions (see Pharma Should Not Settle Off-Label Promotional Suits) has certainly eroded trust in the industry from the public, patients and many physicians.

However, drugs save lives. Even in recent years, we have seen the remarkable difference prescriptions medications have made (HIV, cancer, heart attacks). Also, the majority of prescriptions being used today are now generic, and were made possible because they were once sold under a brand name. As stated above, generics are not always the best choice for patients, and while drug company promotional efforts will undoubtedly increase sales of expensive drugs, this is not necessarily a bad thing if patients' lives are improved. Finally, the way medications are covered and paid for create a sometime perverse set of circumstances where samples and coupons for expensive medicines may actually be in the patient's best interest even if similar medications are available generically or over the counter. Many (especially in the media) want to paint the influence of the pharmaceutical industry as black and white. However, this issue remains very, very grey.

Pharma Should Not Settle Off-Label Promotional Suits

Major headlines were made when it was announced that AstraZeneca Settles Case Over Marketing of a Drug For $520 Million. This is not the first and will not likely be the last off-label settlement by a drug company. The charges from the Justice Department , which the company denies, claim that Astra Zeneca (from Med Page Today) paid doctors for "ghostwritten journal articles that the named authors did not write and reported studies they did not conduct" and "to give promotional lectures to other health care professionals about unapproved and unaccepted uses" for their drug Seroquel (quetiapine) which is used to treat bipolar disorder. Though ghost written articles may not be the best way to promote your product, they are not illegal. In addition, paying physicians to speak about a product is an FDA approved way for drug companies to discuss their products with practicing providers. These activities were not the problem, its that (the Justice Department claims) they were off-label, not on label promotions.

I blogged about what is meant by labeling a while ago in a post called An Indication For Change. Briefly, a physician can prescribe any FDA approved drug for any reason they want. However, a drug company can only promote (sell) that drug for what the FDA says it can be used for. A great example would be Crestor. Back in November of 2008, I blogged about the results of the Jupiter trial (see Jupiter is Out, and the News is Good! ), which showed that in patients who had relatively normal cholesterol levels but high CRP levels, 20mg of Crestor reduced the risk of heart-related death, heart attacks and other serious cardiac problems by 44%. This was a large, randomized clinical trial with important information and the first real trial showing major benefit when a statin was used as primary prevention for heart disease in people with normal cholesterol levels. Despite the exciting news, the Crestor drug reps couldn't talk about it, even though the study was published, and the results were headlines in every major media outlet. This would have been considered off-label promotion. It wasn't until February 2010, when Crestor was approved for primary prevention of cardiovascular disease by the FDA.

I will admit that I do not write Seroquel, and told many of the AZ drug reps who tried to get me to use this drug, that Seroquel was not really a primary care drug, and they would be better off spending their time speaking with the psychiatrists. However, though I am certain one or two rogue drug reps probably bent the rules here and there, given the previous large settlements by other drug companies, I find it very hard to believe that AZ systematically promoted Seroquel for off-label use. As stated AZ denies these claims.

If this is indeed the case, then I believe AZ should fight the claims by the Justice Department, rather than just pay a fine. If you are really innocent, then you will try to prove your innocence at any cost.

As a physician, I understand what settling a case means. The vast majority of malpractice claims are settled. This is because doctors get nervous when their fate is left to a jury to decide between the rich doctor and the injured patient. For physicians, especially given the cost of litigation, it often makes more sense to settle, admitting no wrong, and get on with your practice then to prove your innocence. However, with pharma's deep pockets, cost should not be an issue. Every time a drug company settles a claim for off label promotion, it is saying to patients and physicians "we are not to be trusted." As part of their settlement, AZ will likely have to send "Dear Doctor" letters to all physicians essentially admitting guilt.

Interestingly, The Wall Street Journal is reporting in a post Whistleblower Twice Over: First Lilly, Now AstraZeneca, that the same person who reported AZ to the government (and will pocket $45 million) previously blew the whistle on Eli Lilly who settled a $1.4 billion for off label promotion (he pocketed up to $100 million for that). The fact that the same person blew the whistle on two companies for the same charge (in my mind) calls the entire off-label promotion scheme into question.

This will not be the last big settlement for off-label promotion. The government makes big bucks on these cases, and the drug companies just write a check when fined. If pharma really want to show physicians, patients and the public that it is just trying to make useful medications to help people and not trying to make a profit any way they can, they should fight these claims as hard as possible.

Where have all the journalists gone? More bad reporting on Avandia

I thought journalists were supposed to be impartial, report multiple sides of the story, and only use facts. At least in the case of reporting on prescription medications, Avandia in particular, it seems those "rules" no longer apply.

Today the Wall Street Journal announced that the FDA Weights Halting Avandia Safety Study .
They are basing this report on a Letter written to Sen. Grassley on 3/30 by the FDA commissioner in response to Grassley's findings on the FDA's handling of Avandia. If I were a journalist (and I don't pretend to be one), after reading this letter, the headlines I might have suggested to my editor would have been:

FDA to Grassley: You Have to Wait Until July or
FDA seeks Big Gun in Institute of Medicine to Help with Avandia

Nowhere in the 5 page letter does it say ANYTHING about the FDA considering halting an ongoing study. Here is the particular section that the journalists from the Wall Street Journal are basing their headline on:

"I recognize that head to head safety trials can pose challenging ethical questions. On the one hand, such a trial, by its very nature, must be conducted in the face of a safety concern. One the other hand, if one therapy is clearly inferior to the other, then such a trial should not be conducted, because it would place one group of patients at unnecessary risk."

Though the next paragraph mentions that some experts believe that Avandia is inferior to Actos, the paragraph concludes that some experts, in particular the American College of Cardiology and the American Heart Association, have not come to these conclusions.

I implore you to read the entire letter, and read it in the context that the head of the FDA is writing this letter in response to a Senator who wrote a very public and scathing report on how their operation is run. The report does not read, "thank you senator, we were wrong and will consider stopping this dangerous trial." Rather, what the report actually says is that safety is important to the FDA, in 2005 they became aware of a questionable safety issue but decided it did not warrant going public, when it did (with pressure from Sen. Grassley) the FDA met in July 2007 and decided to keep Avandia on the market, there has been new, more robust data since 2007 which seems to indicate that Avandia is safe, and we have already planned (even before the Grassley report came out) to meet this July to review all the data again.

Read in its entirety, the FDA had already planned to review all of the Avandia data, including the TIDE study in July. The letter to Grassley, that the Wall Street Journal is reporting on, gives no indications that these plans have changed or that the FDA is now considering stopping an Avandia study. If anything, in a very subtle way, the FDA is telling Grassley why the study is needed.

Bad reporting on this subject is not new. In my post More Avandia Scare- Again, Unwarranted back in February, I wrote about New York Times piece that broke the story on the Grassely report. While I do believe the story was worth reporting, the Times failed to mention that everything in the report was from 2007. Both the Grassley report and the Times failed to mention that there was new data, specifically the RECORD trial (see For the RECORD, Avandia does not cause heart attacks, Avandia Vindicated, ) which seems to exhonerate Avandia from any heart risk. This is the real story, that a good diabetes drug continues to get bashed in the media, when a very well done study presented almost a year ago has shown in to be safe.

As referenced above, I believe the real story in the FDA commissioner's letter to Grassley is the fact that they are asking the Institute of Medicine to look into the matter. More importantly, they seem to indicate that the IOM's report will be ready by the July 2010 advisory board. My read on this is that the FDA, based on the scientific data available, feels that Avandia is actually a safe drug. However, given the scrutiny and political pressure they are under, likely believes that anything less than a "pull it from the market" recommendation from the July advisory committee will keep it under fire. Thus, they have brought the impartial and well respected IOM on board. The only reason I can think of for doing this is to back them up on a decision in favor of Avandia.

Here's something to think about:
Because of the media storm caused by Avandia, the FDA now requires any new diabetes drug to prove that it does not cause heart attacks before being approved (see Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III ). These criteria are not surprisingly pretty strict. Based on the results of the RECORD trial, Avandia has now met this new standard of cardiovascular safety, now required of all new diabetes drugs. How will the FDA be able to continue to say that there might be a risk, let alone pull the drug and stop a safety study, when Avandia has now met the FDA's rigid cardiovascular safety criteria?