Thursday, June 26, 2008

If you want to find out the 8 drugs doctors would never take....ask them!

I recently blogged about a particularly annoying article called "8 drugs doctors wouldn't take" that originally appeared in Men's Health and surprisingly appeared on MSNBC, which is usually pretty reputable. There were many annoyances about this piece including incorrect information and re-hashing negative data, much of which has been found to be incorrect. However, the most annoying thing about the story is that it implies that physicians were surveyed about medications they had concerns with, and in fact, I don't think ANY physicians were even asked!

In the orginal Men's Health article, they state:
"Of course, plenty of M.D.'s do know which prescription and over-the-counter drugs are duds, dangers, or both. So we asked them, "Which medications would you skip?" Their list is your second opinion. If you're on any of these meds, talk to your doctor."

Yet there is no mention of how many physicians they asked, how they chose these physicians, etc? In the article there are eight quotes/recommendations by five "experts," three of which came from Philip Rodgers, a Pharm.D (this is no disrespect to Pharm D's who have a great knowledge of medications and their side effects, but article is not titled "8 drugs no Pharm D would ever take").

That last sentence particularly irks me (and many of my colleagues) as well. To sell papers/create buzz, the media reports scary (and in this case, not entirely true) stories about dangerous medications, creating unnecessary worry for patients and headaches for physicians burdened with phone calls after each story hits the press.

I have given my opinion on the safety of the 8 drugs mentioned, but upon further reflection I thought, "What would real doctors say about these medicines?" So, unlike the article, I asked them.

Using Sermo, a physician only social networking site (you must be a licensed physician to join), I posted a question to its 23,000 physician members.

For all of the following medications, please respond whether in an appropriate patient you would prescribe the medication without reservation, with some hesitation due to safety concerns, or would never prescribe the medication due to safety concerns.

Here is a link to the results. After about a day, I got responses from 59 actual physicians. There was overwhelming dissatisfaction with this article, and substantial disagreement with the articles "findings". For all but Ketek, only a few doctors out of the 59 said they would never prescribe these medications. For Advair, 3/4 said they would prescribe without reservation, 1/4 with some hesitation and only 1 said never. For the much maligned Avandia, 2/3 would prescribe without reservation, 1/4 with some hesitation, and only 6/55 physicians said they would never prescribe. Even Celebrex, the Vioxx cousin, though doctors were split on no reservation and some hesitation, only 4/58 said they would never prescribe it. Virtually every doctor said they would prescribe Prilosec and Nexxium without reservation, with only 1 never prescriber.

This is certainly not a scientific survey. However, it is far more scientific then the Men's Health article, asked actual physicians, and is much more reflective of the collective medical wisdom.

Doctors, I hope you will refer patients to this post when they come in asking about the article. Patients, please don't believe everything you read regarding the dangers of medications, especially what most physicians would and would not do.

Special thanks to all my colleagues on Sermo who responded to the question. (Since the survey is still open, I will post the final results on this blog in mid-July).

Sunday, June 22, 2008

The truth on the 8 drugs doctors wouldn't take

Shame on MSNBC for re-purposing this article originally found in Men's Health. This isn't even a survey of physician's experience with these supposedly dangerous drugs, and the expert most commonly quoted in the article is a pharmacist, not a physician. I recently mentioned the original article a week or so ago, when I posted about one of my asthmatic patients who was quite well controlled on Advair but wanted to stop the medication, because her husband had read the report. In hopes that other patients won't similarly be worried about these medications, I have listed the supposed dangers and the truth behind them below.

As a physician, these kind of reports really anger me. I am sure they sell magazines or newspaper, but cause needless worry for patients and potential harm. For example, for those patients taking Avandia, sales data indicate that though some patients switched to other agents when media reports surfaced about a potential harm, many patients simply stopped taking Avandia. In many cases, patients stopped the medication, without consulting with their physician. This would cause their sugars to go up, potentially causing many complications. I am really surprised that a legitimate news organization like NBC would post such a piece on its website.

Their claim: Advair "may contribute to as many as 5,000 asthma-related deaths in the United States each year."

The truth: This stat comes from the discussion section of a publication that did an analysis of studies (meta-analysis) containing salmeterol, a component of Advair. The truth is that study never answered the question of Advair safety. I outline all of the data in my recent post Good News for Asthma Patients, but the bottom line is that issue really only concerns salmeterol taken alone. When taken together with fluticasone (Advair is fluticasone +salmeterol) not only is it safe, but it is also one of the most effective medications for asthma. Since the introduction of medications like Advair the asthma death rate (4,000 is the correct number) has actually declined, not increased!

Their claim: For the diabetes drug Avandia (rosiglitazone) "people who took rosiglitazone for at least a year increased their risk of heart failure or a heart attack by 109 percent and 42 percent."

The truth: Avandia (and other TZD's like Actos) do in fact increase fluid retention that can lead to heart failure in those at risk. This is a well known and uncommon side effect that can be avoided if these medications are used appropriately. The heart attack risk, which comes from another meta-analysis (notice a trend here), that just simply isn't true. I discuss all the recent studies and analysis in my recent post Avandia Vindicated!

Their claim: People taking 200 mg of Celebrex twice a day more than doubled their risk of dying of cardiovascular disease

The truth: This is one of two drugs out of the eight that doctors might not actually take. The real heart attack risk was seen in Vioxx, which was why it was pulled from the market. The question of cardiac risk with Celebrex, being a similar drug, has been studied, and no conclusive risk can be found. However, more importantly, it doesn't seem to be any more effective than ibuprofen and naproxen, and it's benefit of not causing the stomach ulcers which can be caused by ibuprofen and naproxen is not as substantial as initially thought. Because of a possible risk of heart problems, and no clear benefit over generic drugs, most doctors probably wouldn't recommend Celebrex as a first line agent. That said, certain patients who do well on it shouldn't all of a sudden stop this medication, because their is no clear heart risk.

Their claim: "This antibiotic, which has traditionally been prescribed for respiratory-tract infections, carries a higher risk of severe liver side effects than similar antibiotics do."

The truth: This is the other drug that doctors probably wouldn't recommend. The reality is that ALL antibiotics are over-prescribed, and there are now very resistant bugs in the community that were once limited to the hospital. The good news is that azithromycin, amoxicillin, ciprofloxin, and others are all generic, work well, and are pretty safe. However, they should used sparingly. Ketek, if ever used, should reserved for only rare infections where any of the other older, generic antibiotics wouldn't be used.

Prilosec and Nexium
Their claim: " The FDA has investigated a suspected link between cardiac trouble and the acid-reflux remedies."

The truth: What????? Even they say the FDA found no evidence of a link. Sometimes heart burn symptoms can really be a heart attack, and taking these medications might delay the diagnosis of someone with an actual heart problem. However, this doesn't mean the medications aren't safe. Prilosec is even over the counter. Both are extremely effective in suppressing acid and making miserable patients happy. The link between acid suppression and pneumonia is unclear, and this is really only for people who are hospitalized or otherwise at risk, such as nursing home patients. They have been shown to be substantially better than H2 blockers such as Zantac. I don't think I know a physician that WOULDN'T recommend Prilosec or Nexxium to a patient with acid reflux.

Their claim: "Overuse of the active ingredient tetrahydrozoline can perpetuate the vessel dilating-and-constricting cycle and may cause even more redness."

The truth: OK, but so what. Almost every over the counter medication states how much and how often you should use a medication. There are many medications that if overused, or not used correctly, can cause problems. This doesn't mean that physicians wouldn't recommend Visine or similar OTC eye drops.

Their claim: "pseudoephedrine doesn't just constrict the blood vessels in your nose and sinuses; it can also raise blood pressure and heart rate, setting the stage for vascular catastrophe."

The truth: Pseudoephedrine was one of the most common medicines used in cold medications until some kids started making crystal meth with it. You can still get this, but it is placed behind the counter. Most cold medicine makers replaced Pseudoephedrine with phenylephrine, another decongestant, which doesn't work quite as well. Even Sudafed doesn't have pseudoephedrine in it anymore! These medications have been taken by millions of people for many years, and there have been no reported dangers. They can raise your blood pressure, which could be a concern if you already have high blood pressure. However, for most people they are quite safe and shouldn't be listed as a "dangerous" medication.

Friday, June 20, 2008

Save Thousands On Your Health Care

ABC News recently posted a story about how you could Save Thousands On Your Health Care. Though theoretically, a helpful story with a few good suggestions (like negotiating your co-pay for a hospital admission with the hospital), many of the suggestions really only apply to patients who don't have health insurance (or the few that use an HSA), and some are not good, such as saving money by splitting pills which can work, but can also be ethically tricky for the doctor who is being asked to write an incorrect prescription. Most of the patients that I see use their health insurance to pay for their health care. There biggest cost is their out-of-pocket expenses, which (since you can't bargain down your deductible or monthly payments) is usually co-pays for prescriptions. Here are a few suggestions that might actually help patients save money by lowering their out of pocket expenses.

Know your formulary
Your insurance company generally will use a Pharmacy Benefits Manager (PBM) to negotiate prices with the drug companies. Most patients have a three tiered prescription benefit such that generics are the lowest co-pay, preferred drugs cost more ($15) and non-preferred drugs cost a lot ($35). Unfortunately, differentiating which drug is on which tier is not always easy, and it changes on a regular basis (just like in the supermarket when Coke is on sale one week and Pepsi the next). We use an electronic medical record which gives us this information and updates it regularly. Most physicians don't have that luxury, and it is impossible to keep up. My previous post on the new CFC asthma inhalers is one example of how crazy this can be. Another example is for federal employees, the nasal steroid Veramyst is a generic co-pay, but the generic for Flonase (fluticasone) is a non-preferred tier: prescribing a generic will cost these patients more in this case! Since physicians can't keep up, you need to know your formularly. This can usually be found on your insurance's web site. If you are paying the highest co-pay, there is almost always another alternative. Before you fill a new prescription, be sure you know where it is on your formulary.

Don't Wast Money on Things That Don't Work
Patients take a lot of over-the-counter medicines, supplements, and other things that may not have any benefit, and may even harm them. I can't tell you how many patients have asked me about colon cleansers which provide no benefit, and may even produce harm. Tell your doctor about everything you take for your health. Don't be embarrassed. Many of the products out there are not clearly harmful, and may even be beneficial, but if you are trying to save money, may not be worth the price of your hard earned dollar. I have blogged previously about the lack of proven benefit of vitamins and supplements. At most, a generic multi-vitamin (plus calcium and vitamin D for women) is likely all you need.

Shift Things Back
One of the reasons insurers are so glad that Zyrtec and Claritin are over the counter, is because they don't have to pay for them. They have thus shifted the cost back to you. These branded medicines are quite expensive. If you have to takes these infrequently, the generic equivalents are probably OK. If you are taking them on a regular basis, most guidelines would suggest that the more effective agent would be a prescription nasal inhaled steroid (like fluticasone). The inhaled steroid market is now fiercely competitive with Veramyst and Omnaris added to the others (Nasonex, Rhinocort, Nasacort). With both of these new drugs, you can actually get coupons so that your co-pay will be as low as a generic. Thus, you will be getting appropriate and better treatment for a fraction of the cost. Antacids (Prilosec, Zantac) are another example.

Ask for Coupons
As above, your physician not only has samples for medications, but also will often have coupons to defray your co-pay cost. Ask for these. Lipitor is the number one cholesterol drug in the country, and with simivistatin now generic, insurers will be pushing you to use this instead of Lipitor to lower your cholesterol. However, both Pfizer and Astra Zeneca (makers of Crestor) have coupons to offset the cost differential for you (it may even be cheaper then what you would pay for the generic). There is no question that samples and coupons increase the overall cost of prescriptions by encouraging physicians to write newer drugs and fewer generics. Thus, you may have a moral objection to this method. However, if you are trying to save money for yourself, this is one way.

Use Generics
Speaking of generics, you SHOULD use them when possible (especially if their is no formulary or coupon disincentive not to). I have many patients fearful of using generics, because they think they are less effective. Generics are almost always just as good as the branded products. Certain medications where the dose needs very fine adjustments, such as hormones (estrogen, thyroid) and blood thinners (warfarin/coumadin), this difference may make a difference. However, most of the time the generics are just as good, and some retailers are now charging you only $4-5 for them.

Stop Smoking
I know this has nothing to do with saving money on prescriptions, but 21% of adult Americans still smoke. With a pack of cigarettes averaging about $5 a day, patients could save over $1800 a year if they just stopped smoking.

Tuesday, June 17, 2008

Two studies: Coffee Consuimption and Prostate Cancer Prevention

Coffee associated with lower risk of death
A study just published in the Annals of Internal Medicine called The Relationship of Coffee Consumption with Mortality looked at 41 736 men and 86 214 women from the Health Professionals Follow-up Study and Nurses' Health Study. They found that men and women who regularly drank a few cups of coffee each day were slightly less likely to die then those that did not drink coffee regularly, mainly due to fewer deaths from cardiovascular disease.

So, should you drink coffee to prevent death?
Not necessarily. These type of studies are called cohort studies, where a group is examined for a period of time to try and ascertain whether or not something is associated with a disease. However, association and cause is not necessarily the same thing. For example, people who attend NASCAR events (sorry racing fans) are more likely to smoke. However, just by attending a NASCAR event doesn't cause you to smoke. There are clearly other factors involved. The researchers tried to control for these factors by taking into account many factors that may have played a role in association between life expectancy and coffee including: smoking status, body mass index, physical activity, alcohol intake, use of hormone therapy for women, parental history of myocardial infarction, and dietary factors. Given this, the results should be considered. However, the only way to prove that drinking coffee will prolong your life would be to do a study with non-coffee drinkers and randomize them into two groups: those that would start drinking coffee and those that continued not to drink coffee.

Bottom Line: At a minimum, the study suggests that there is no inherent risk of drinking coffee. If you drink coffee you probably don't need to stop. However, if you don't drink coffee, there is really no compelling reason to start. For coffee drinkers, also remember that though coffee doesn't have any calories, the other things you put into that coffee do, and these calories can increase your risk for weight gain, diabetes, and possibly death.

Prostate Cancer Prevention.
The New York Times did an excellent job explaining some interesting new findings recently published on some old data from an old but controversial study. This well done study showed that finasteride, a now generic medication used for shrinking men's prostate to relieve the symptoms (BPH) was also associated with about a 25% risk in new prostate cancer. Given that prostate cancer is the 3rd leading cause of cancer death in men, why did physicians not start giving all men finasteride back in 2003, when the study was published? Because of the finding that the more of the tumors that did occur in men taking finasteride were a higher grade, and thus theoretically more dangerous. One of the controversies with prostate cancer is that of the many men who have prostate cancer, most will die of something else. The evidence that screening for and then treating prostate cancer in order to save peoples lives is controversial, and not all physician groups even recommend that men get an annual exam and PSA test.
Thus, from the NY times:
"The concern was that the drug might be preventing cancers that never spread. At the same time, finasteride might actually be causing aggressive cancers that can kill."
However, the conclusions in the 2003 paper were based on prostate biopsies, which only look at tiny pieces of the prostate. Most of the men where prostate cancer was found had their prostates removed, and so the researchers over that last several years have painstakingly looked at all of these prostates and found that taking finasteride reduced the risk of having any tumor, aggressive or non-aggressive.

Bottom line: This is very compelling evidence that suggests men should take finasteride to prevent prostate cancer. The medicine is now also generic, so cost is not an major issue. In addition, many men do develop symptomatic BPH, which the drug can also treat. There are side effects, including sexual dysfunction, so this should be taken into account.

Monday, June 9, 2008

Avandia Vindicated!

I suppose with the flurry of press on the ACCORD and ADVANCE trials presented at the ADA, the third similar study, the VADT, did not garner that much excitement in the media, with barely a mention. But the one headline from the good folks at MedPage today clearly caught my attention: VA Diabetes Trial Appears to Vindicate Rosiglitazone (Avandia) Safety

This 3rd trial was consistent with ACCORD and ADVANCE (which I blogged recently) in that it was unable to prove that aggressive diabetes management improved rate of heart attack and stroke. However, like the two prior studies, the expected event rate was lower than anticipated (likely due to better control of cholesterol and blood pressure) indicating in my opinion good news for the overall management of diabetes. However, unlike the Triple Crown, this 3rd leg did not disappoint with news about Avanida. However, before getting to this, let's review.

In May of 2007, Dr. Steve Nissen published a meta-analysis of diabetes studies containing Avandia. This now famous (or infamous) study started the entire Avandia safety controversy. Dr. Nissen analyzed 42 randomized trials lasting over 24 weeks involving Avandia, and found a 43% increase in risk of for myocardial infarction (for you stat folks, odds ration for MI was 1.43, 95% confidence interval [CI], 1.03 to 1.98; P=0.03).

1. Discrediting Nissen's study. In addition to concerns about how quickly the study was published in the NEJM and the political nature of the study's use as a lightning rod to shape public policy, scientific holes in the analysis were also raised. Diamond, et. al did a re-analysis of the same data published in the Annals of Internal Medicine in October 2007, and found no difference in heart attacks. As a side note, no scientist or statistician has ever been able to explain to me how if the rates of myocardial infarction were 0.58% in the Avandia group and 0.62% in the non-Avandia group, how it could be possible to have a 43% increase in myocardial infarctions with Avandia.

2. RECORD. The FDA had known about the concerns of myocardial infarctions, and was likely the primary source of Nissen's investigation. However, they were apparently holding off on any decisions, because the RECORD study, a large, randomize prospective trial to answer the very question of cardiac effects of Avandia was ongoing, and interim monitoring of the study seemed to indicate no cause for concern. However, when Nissen went public and started all the controversy, the RECORD investigators felt obligated to respond, and on July 5th, 2007, preliminary data from the RECORD study was published in hopes of answering any Avandia concerns. This study looked at over 4000 patients with uncontrolled diabetes not previously on Avandia. Half received Avandia and the other half did not, with the primary outcome of cardiac events. After 3.75 years there was no difference in heart attacks in the patients taking Avandia the on those not taking the medication. Not one, but three editorials accompanying the article suggested that these findings were not reassuring because the study was not statistically powered to show a difference.

3. The FDA investigates. In response to the controversy, and pressured by Congress, the FDA extensively reviewed Avandia safety data. In addition to a meta-analysis similar to Nissen's, the FDA looked at RECORD and two other large, randomized prospective trials; ADOPT (which showed Avandia to be superior to metformin and glyburide in keeping diabetes under control) and DREAM (which showed Avandia to prevent diabetes in patients who were at risk). These studies combined or individually, along with retrospective analysis from large data sources did not show any risk for Avandia related to heart attacks. In November 2007, the FDA added a boxed warning to Avandia which mentioned data discussed in Dr. Nissen's meta-analysis as well as data from ADOPT, DREAM and RECORD, stating, "In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

4. ACCORD is stopped. In February of 2008, the intensive arm of the ACCORD study was stopped because of increased deaths. Since the results were just presented, we know that in the over 10,000 diabetics studied for 3.5 years, there was no difference in intense vs. usual care for prevention of heart attacks, and in fact there were more deaths in the intense group. According to the study, more than 90% of the patients in the intense group were taking a TZD (almost all Avandia) and more than half the patients in the standard care groups were taking a TZD. Three accompanying editorials to the recently published results imply that since more patients were on Avandia in the intense group, this might account for the increased risk of death in the intense group. However, we know this not to be the case because when the ACCORD was stopped, the NIH specifically looked at Avandia and found this not to be associated with increase risk. “Because of the recent concerns with rosiglitazone, our extensive analysis included a specific review to determine whether there was any link between this particular medication and the increased deaths. We found no link.”

5. VADT. June 8th, 2008, the results from the Veterans Affairs Diabetes Trial (VADT) were released. This study also looked of almost 2000 veterans for almost 8 years similarly found no improvement in heart attack and stroke in the intensively treated group as compared to the standard group. However, like the previous studies, the rate of cardiovascular events was substantially lower than expected, and about 80% of the patients in both groups were taking Avandia. When the investigators presented their results of their analysis at the ADA meeting, these results showed that, if anything, Avandia may have actually prevented heart attacks!

What does this all mean?
The gold standard for research is a large, prospective, randomized clinical trial (RCT). This is considered one of the best ways to answer a question about whether a drug causes a side effect or an improvement. A meta-analysis is done when large RCT's are not available. Meta-analysis uses statistical techniques to combine data from smaller trials in an attempt to statistically replicate a large, prospective RCT. Since Dr. Nissen's meta-analysis showing risk with Avandia that is fraught with controversy, we have had multiple large, prospective, randomized clinical trials that show the opposite result. Between RECORD, ADOPT, DREAM, ACCORD and VADT; there have been over 26,000 patients 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. I think it is clear based on the inherent limitations of Nissen's findings and the substantial evidence from the aforementioned studies that Avandia is not, and has never been associated with heart attacks or myocardial ischemia.

Saturday, June 7, 2008

ACCORD and AVANCE: Good News for Type 2 diabetes...really.

At least according to what's out there in the media and in the medical blogsphere on the two large recent diabetes trials presented at the ADA and published in the NEJM, in my opinion everyone seems to have missed the big picture, and the good (not bad) news about diabetes.

Just look at the headlines:

NY Times: Tight Rein on Blood Sugar Has No Heart Benefits
AP: Intense diabetes therapy didn't cut heart problems
MSNBC: Aggressive diabetes care doesn't prevent deaths
and my favorite
Forbes: Not So Sweet

Even Dr. Centor, in an excellent commentary on how the findings of these studies relate to problems using performance measures (which I agree with), does not mention anything positive..

The issue at hand is that though we use the hemoglobin A1c, a measure of overall sugar control, as a target for diabetes treatment which has been proven to prevent small vessel (microvascular) diabetes complications such as blindness and kidney problems, we have never proven (with scientific rigour) that it prevents larger vessel (macrovascular) disease such as heart attacks and stroke. The thought was that if there was a large study that treated even more aggressively (target A1c is usually recommend at less than 7%, normal A1c which is not currently a target is less than 6%), this might prove the point.

The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) looked at 10,251 type 2 diabetics (more than a third with a prior stroke or heart attack) with a median hemoglobin A1c of 8.1% and randomized them to receive intensive therapy (targeting an A1c below 6.0%) or standard therapy (targeting an A1c from 7.0 to 7.9%). At a year the groups achieved A1c's of 6.4% and 7.5% respectively, but after several years there was not real difference in combined hearts attacks, strokes or deaths in either groups (352 vs. 371), there was a statistical difference in death (257 vs 203), and the intense arm was stopped early.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was a similarly designed European study 11,140 patients with type 2 diabetes, except the targets for the intense group was less than 6.5% and not less then 6.0%. Interestingly the A1c's achieved by both sets of patients was nearly identical to ACCORD (6.5% vs.7.3%). The also found no difference in combined heat attacks, strokes and deaths; but fortunately found no difference in deaths from the intensive group as seen in ACCORD.

All of the reports (linked to above) point out that these studies failed to prove that aggressive treatment makes any difference in heart attacks or strokes, and in the case of ACCORD seemed to (surprisingly) cause more heart attacks. However, they are missing a majorly important finding of both studies. Treating diabetes aggressively is quite effective!

We already knew about microvascular disease, and ADVANCE showed us that this still holds to be true, with substantial reductions in early kidney disease. However, what is being overlooked is that both groups in both studies did much better than expected. In ACCORD, to show a statistical difference, the study enrolled enough patient based on research about event rates in diabetics. Based on their original calculations, there should have been about 500 heart attacks or strokes in the standard care group. However, there were only 371 in the standard care group, and even fewer in the intense arm. Death calculations were not published in the article, but I would imagine that though the death rate was (seeming paradoxically) higher in the intense arm, death rates in both arms were likely much lower than one would typically expect. Similarly, in ADVANCE, the found that after a mean of approximately 3 years of follow-up, it became apparent that the event rates (in the two groups combined) were lower than expected, and had to adjust their protocol, extending it by a year. Fewer events than anticipated in two very large studies seem like good news to me.

Why would these studies find lower event rates than expected? Likely because of more aggressive overall treatment. Not just lowering sugar, but lowering blood pressure and cholesterol levels with medications. In fact, because cholesterol and blood pressure reduction may be such important factors for macrovascular complications in diabetics, it might take a greater number of patients and a longer amount of time (not lowering the sugar to normal) to show the true impact, which is likely beneficial. Thus, patients with Type 2 diabetics should be relieved and not fearful of these reports. We have better medications that are more effective at lowering not only sugar, but also blood pressure and cholesterol and together (along with diet, exercise, and an aspirin) lower bad outcomes including heart attack and stroke, then we were previously able to accomplish just a few short years ago.

Why the difference in deaths?
There will be a lot of opinions about why patients in the intense arm of ACCORD had an increase number of deaths and ADVANCE did not. Here is mine.

The first two of the three the editorials which accompany both studies published in the NEJM note that most of the patients in the intense group were on a TZD like Avandia (the 1st and 3rd editorial both cite Dr. Nissen's well publicized/criticized meta-analysis about cardiovascular risk with Avandia-also published in NEJM), together suggesting that maybe the increased death rate was due to this class of medications. However, we know that TZD use can not account for the differences in outcomes in ADVANCE because as I have noted in a previous post on this study, when the study was stopped, given the concerns regarding Avandia, the NIH specifically looked for links to Avandia and found none. (It is interesting that this is not highlighted in article.) In fact, since most patients in the intense arm were taking a TZD like avandia, and heart attacks were lower, and increase in deaths could not be attributed to rosigliataozne, this should be most reassuring (see, more good news).

If not Avandia, then why the increased death rate in ACCORD but not ADVANCE. The second NEJM editorial points out that the rate of A1c drop was much more rapid in ACCORD then ADVANCE (1.4% within 4 months vs. 0.5% at 6 months respectively). How did they achieve such a rapid drop in one study, but not the other? This is reiterated in the discussion section of ADVANCE.

"Mechanisms speculated to underlie the excess mortality found with intensive glucose control in the ACCORD trial include the initial level of glycated hemoglobin, the degree and pace of glucose lowering, and the treatments used to achieve such lowering.20,22 In the ADVANCE trial, no subgroup of participants was identified to have evidence of an adverse effect of intensive glucose lowering on major vascular outcomes, including the subgroup with an initial median glycated hemoglobin value similar to that in the ACCORD study population.21"

Exactly how doctors tried to achieve normal A1c levels in Type 2 diabetics was not clarified in the ACCORD publication, an in fact, investigators could use their own clinical judgement. However in ADVANCE, this is spelled out clearly and in step wise fashion:

1. Add gliclazide (and SU like glyburide or glimeperide, but not used in the US)
2. Increase the dose of gliclazide MR (30-120 mg)
3. Add or increase the dose of metformin;
4. Add orincrease the dose of thiazolidinedione;
5. Add or increase the dose of alpha-glucosidase inhibitor;
6. Add bed time insulin therapy;
7. Add a full insulin regimen or increase the dose of a full insulin regimen

What you see hear is that in ADVANCE, adding insulin was the last resort in a stepwise fashion to get the A1c under 6.5%. Again, we don't know exactly what happened in ACCORD, but if you look at the differences in medications not only was there more TZD's in the intense group, there was a large difference in insulin use (77% in the intense group vs. 55% in the standard group). In ACCORD the rates of insulin use was 40% in the intense group and 24% in the intervention group. Hypoglycemia and weight gain (which are both caused by insulin) were reported as significantly increased adverse events in ACCORD.

Thus, I would argue that one of the reasons you might actually cause harm in intensively trying to lower sugar, is when you need insulin to get to that goal. This suggest (contrary to the ADA guidelines) that targeting to an A1c of less than 7.0% should be done with multiple medications, and not with insulin. In fact, it might be better to reserve insulin for those patients with an A1c of more than 8%, despite multiple oral agents (again, contrary to ADA guidelines).

Tuesday, June 3, 2008

Good News for Asthma Patients

I saw a patient yesterday, with previously poorly controlled asthma, who has now been under excellent control for years on Advair. She made an appointment to see me to discuss a concern she had. Her boyfriend saw an article in Men's Health about 8 drugs doctors would never take, and Advair was number one of the list. Though this is not the first or last misinformed report on the safety of asthma medications, I am hopeful that a soon to be published in the Annals of Internal Medicine will hopefully calm the fears of patients (and even some physicians).

The study looked at the safety of salmeterol when combined with an inhaled corticosteroid (ICS). The full report is currently embargoed, but the study is an analysis of of 66 studies with over 20,000 patients with asthma which showed that when the long-acting beta-agonist (LABA) salmeterol was combined with ICS it not only decreased the risk for severe exacerbations, but also did not increase the risk for asthma-related hospitalizations, deaths or intubations compared with patients who only used ICS alone.

There are currently two combinations products of an ICS and LABA, Advair (the 3rd most common prescribed drug in the US, with almost $4 billion in sales) and Symbicort (new to the market in the US, but used throughtout the world for years). ICS are the preferred treatment of asthma according to World Health and US asthma guidelines for both adults and children. In addition, for those patients who can not be controlled on ICS or have moderate persistent asthma, the combination of ICS and LABA are the most effective agents.

The controversy (and subsequent media frenzy) all started with the release of the The Salmeterol Multicenter Asthma Research Trial or SMART study which was designed to show safety of salmeterol. 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. However, by the time the study was finished, it was clear to most experts that LABAs should not be used alone. In fact, for the patients in the SMART study who were taking both ICS and salmeterol, there was no increased of death or worse asthma.

This makes a great deal of sense because asthma is predominantly a disease of chronic inflammation. When you treat the symptoms alone with a LABA but don't treat the underlying inflammation with an ICS, it is not a surprise that some people will have increase risk of serious asthma attacks and even death. The problem is that from the FDA's perspective, in order to prove that taking ICS plus LABA (i.e Advair, Symbicort) was just as safe as LABA alone, you would need to do another large, randomized trial. The SMART study would have needed 60,000 patients if it had gone to completion, so a study comparing ICS plus LABA to ICS alone looking at asthma hospitalization and death would need well over 120,000 patients since the risk for these events is so low. It does not appear that the NIH or other government agency would sponsor such an expensive study, and the pharmaceutical industry would similarly not be willing to make such an investment just to prove a point (that most doctors realize anyway). Thus, combination products like Advair and Symbicort will continue to have a boxed warning.

However, the new study soon to be published in Annals adds a considerable amount of reassurance. Since a randomized trial is virtually impossible, a meta-analysis (combination of similar studies) is the next best step. A previous meta-analysis (which received a lot of media attention and is mentioned in the Men's Health article) showed an increased risk, but 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. This new meta-analysis looks specifically for the risk of adding a LABA to an ICS. The fact that patients did better on the combination therapy confirms consistent data that the ICS plus LABA is better then ICS alone or other combinations. In addition, the fact that there were no additional deaths, hospitalizations or intubations is good evidence that though LABA's may be dangerous when used alone or with other asthma drugs, the appear to be safe when used in combination with an ICS (i.e Advair, Symbicort).

I am hopeful that when the article is released in its entirety, that it will receive at least half as much press as all of the other reports. Somehow, I doubt this.