Monday, March 31, 2008

Vytorin and Singulair: Problems for the Company, Confusion for the Public

Much has happened in health related news in the past week since I have been away. In my mind, most notably news about Singulair and Vytorin; ironically both Merck products.

FDA looks into Singulair, risks of suicidal thoughts
As reported by USAToday and other sources, last week, the FDA announced this early communication about reports about possible links with the popular asthma and allergy drug and suicidal thoughts. Similar to previous post about the Spiriva warning, and my initial post when the FDA decided to release these warnings, this is another example of information that is really helpful to no one, confusing to patients, and disastrous to physicians who will be bombarded with phone calls from concerned patients and parents. Though reports of possible suicidal though are very serious and should certainly be investigated, such a warning is premature. Singulair is extremely common, with millions of prescriptions sold, so if there really were a link to suicidal thought and this medication, we would probably know about it by now. There is no real biologically plausible explanation for the connection.
Bottom Line: Singulair is a very clean and safe drug, and this report is no reason to stop it.
What you will not hear elsewhere: Though Singulair is likely safe, it is ridiculously over prescribed. Singulair is indicated for the treatment of allergies and asthma. For allergies, It has not been shown to be more effective than Claritin (which is now generic and over-the-counter). In fact, when Merck-Schering were trying to add Singulair to Claritin, they found it no more effective than Claritin alone (sound familiar?). In this case, they decided not to manufacture this new pill. The most effective agents for allergic rhinitis are inhaled nasal corticosteroids. Flonase is now available as generic fluticasone, and is much more effective then Singulair (which is not generic), Claritin or the combination of the two. Regarding asthma, the updated 2007 NIH guidelines recommend inhaled corticosteroids for asthmatics of all ages. The data is overwhelming, clear and convincing. Singulair, which has much less of an effect is considered alternative therapy by the NIH. Yet, Singulair remains one of the most commonly prescribed drugs for asthma.

More on Vytorin
Despite all the "shocking" headlines, from CNN to ABC news, there really isn't anything new here. My favorite was the video from the Today Show on NBC that titled this a "health alert." However, this story clearly hits home for many. My post on the letter I received from Merck on this matter has thus far been my most viewed post. The results that were reported in the latest cardiology meeting and in the New England Journal simultaneously confirm what was announced in January. Vytorin (zetia plus zocor) did lower cholesterol more than Zocor alone, but there was no difference in its ability to prevent clogging of the arteries. This is important news because this means that there continuing evidence that there may be more to the cholesterol story than just lowering "bad" cholesterol or ldl.
Bottom Line: Though the news does reinforce not using Vytorin as initial therapy, it does not mean that Zetia is completely useless. Some patients have side effects from statin medications, and if they can not take a statin (or take it at a dose they need to lower their cholesterol), then Zetia currently the best option.
What you will not hear elsewhere: There will be multiple comments about how Merck promoted this drug (remember the ads with family members dressed to look very similar to cholesterol containing foods?). The New England Journal has a very interesting piece on the differences in use of Vytorin and Zetia between Canada and the US, which (correctly) suggests that much of this may be do to direct to consumer advertisement (which is not allowed in Canada). However, what is not discussed is that one major determining factor in what a physician prescribes for their patient is which drug happens to be preferred by their insurance company's prescription formulary. The only patients I wrote prescriptions for Vytorin for were my patients who had Aetna insurance. Until very recently, if you were an Aetna patient, the only cholesterol lowering options you had were Zocor and Vytorin. Thus, for those patients who needed a stronger statin the Zocor (such as Lipitor or Crestor-Crestor is now finally on Aetna's formulary), I had no choice but to go with Vytorin, despite limited data. Why would Aetna choose this over Lipitor (the most popular cholesterol drug) or Crestor (new kid on the block)? Merck had obviously given Aetna a much better price then the competition on their cholesterol lowering drugs.
Finally, don't throw out surrogate markers just yet. Even more evidence that LDL cholesterol may not be the only thing that is important, just announced in the Wall Street Journal today that Astra Zeneca was stopping a Crestor trial early because patients clearly benefited from the drug. The Jupiter trial (which we were involved in) took patients with relatively normal LDL cholesterol, but high CRP levels (which have also been associated with increased risk) and randomized them to placebo or Crestor 20mg. Though the results have not been published, clearly a significant amount of patients taking Crestor had fewer heart attacks or strokes.

Friday, March 21, 2008

Spring Break

I will be out of town for spring break, but back in the office and back blogging next week.
Stay well.

Tuesday, March 18, 2008

Spriva and Stroke: FDA warnings create buzz and confusion

It only been a few hours since the FDA's warning on Spriva (an inhaler used for patients with Chronic Obstructive Pulmonary Disease or COPD) but there are already postings on the Wall Street Journal and AP ; and the night is still young.

As I warned when this initiative by the FDA was first announced:

Increasing public awareness about potential adverse reactions is a good thing, but please do not be alarmed every time you hear on the news that there is a new warning about a particular drug.

Though the Spiriva warning is not the first warning since this initiative, it is likely the first one that will get significant press. Specifically, the warning states that:

"ongoing safety monitoring has identified a possible increased risk of stroke in patients who take Spiriva (tiotropium)...... Boehringer Ingelheim reported to the FDA that it has conducted an analysis of the safety data from 29 placebo controlled clinical studies (“pooled analysis”)....(which showed) the preliminary estimates of the risk of stroke are 8 patients per 1000 patients treated for one year with Spiriva, and 6 patients per 1000 patients treated for one year with placebo. It is important to interpret these preliminary results with caution (my bold)."

Before further explanation, I want to point out that according to the FDA's statement:

-pooled analyses have inherent limitations and uncertainty

-Patients should not stop taking Spiriva

What's going on???

Once a drug gets approved, the company that makes it is required to report analysis of studies and determine if any potential risks exist. In the past, the communications stayed between the FDA and the drug company to determine if the risks were real, whether further investigation was needed or whether action should be taken. However in an effort to communicate to the public about early potential risks (or look like they were actually doing something to improve drug safety), the FDA decided to make these communications public.

What is a pooled analysis?

If a side effect occurs once in 10,000 patients taking a drug, you may need to give the drug to 30,000 patients before someone would have the side effect. Drug companies do many kinds of studies to investigate their drug before and after it is approved, but these studies are much smaller. By looking at all of these studies together, you might be able to see a rare side effect. The problem is that squishing all these studies together has its limitations, because the designs of the studies are quite different. Let's say that you were trying to prove that an apple a day keeps the doctor away. In 100 schools across the country, you gave half the students apples. In each school, there was no difference between the apple eaters and non apple eaters, but when pooled together, apple eaters were actually found to have more doctor visits. Apples must be harmful, correct? It depends on what schools (pre-schoolers are more likely to be sicker then high schoolers), when the study was done (fall worse than spring), number of students studied, and lenght of the study. If all things were pretty similar, then the study might have some merit. However, most of these pooled analysis do not use similarly designed studies, and can sometimes generate inconclusive data that scares people to death (see Avandia below). In this example, there could be more doctors visits in the apple eaters, but most of these visits could have been disproportionately represented by the one pre-school in the study that looked at doctor visits from September to December.

Does Spriva cause stroke?

It might. It might also cure cancer, but in both cases it just isn't clear. In 29 trials included data from about 13,500 COPD patients, there was a difference of 2 strokes per 1000 patients taking Spiriva for a year. This is a low number, and in a pooled analysis should be taken with a huge grain of salt. There is no biologically plausable reason for Spriva to cause a stroke. The best way to determine whether or not there is an issue is to do a large, controlled trial. This trial called UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium) is actually underway, and the results are expected to be released in June. Why not wait a few months for the findings of this study before releasing data to the public? Though Spriva is not life saving (nothing but quitting cigarettes will save the lives of patients with COPD), but it does improve lung function and improves quality of life for patients.

My recommendations:

If you have COPD, taking Spiriva, and it is helping you breathe then by all means continue to take it. The FDA release give such little information that your doctor will not likely be able to tell you much more, and may suggest stopping it simply because he or she is too worried about getting sued.


If this sounds familiar, it is. The same type of data was reported by GSK to the FDA on heart attacks with Avandia. GSK's large, randomized controlled trial to actually answer this question was ongoing, and so the FDA (correctly) chose to wait before alarming the public and drawing any incorrect conclusions. However, someone inside the FDA didn't like that idea and alerted Dr. Steve Nissen (of Vioxx fame, and now a frequent sound bite on any potential drug danger). Because of a settlement on another product, all of GSK's data was available online, so Dr. Nissen did his own analysis and got it published in the New England Journal of Medicine in a mere 3 weeks time (normal turnaround time is months). This created a media frenzy, which naturally scared doctors and patients (we recently looked at our own prescription data, and after this press release many of our patients stopped taking Avandia on their own, before speaking with their doctor). After several meetings and analysis, it turns out that in well done, large clinical trials, there is no risk of increased heart attacks with Avandia. Trying to determine what to do between the intial warning and subsquent findings, in November 2007 the updated Avandia's label and released a statment saying that:

FDA has concluded that there isn't enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes.

Of course this doesn't get nearly the press that the scary 5/07 release got.

My guess is that when UPLIFT shows no increase stroke with Spiriva, you won't here about that either.

Sunday, March 16, 2008

Quick Takes: Things that don't work.

What is often reported in studies is what works. What is often reported in the media are those studies, plus anything about dangerous side effects.
Here are a few recent reports of negative studies, or studies where the treatment was found not to work. These studies are sometimes just as important as positive studies, because patients can avoid unnecessary cost and side effects for treatments that aren't effective.

Sleep-Disordered Breathing in Kids May Recur a Year After Adenotonsillectomy
A study in The American Journal of Respiratory and Critical Care Medicine looked at predictors for failure of adenotonsillectomy for children with sleep disordered breathing. This is one of the most common surgeries for children. The found that the biggest predictors of failing the surgery at one year were obesity as well as African American race. About half the children had sleep disordered breathing at one year, and almost 1/3 who had surgery were actually worse then before the surgery. The authors of the study concluded that closer follow up is needed for these children. I would add that you really need to address the problems of sleep disordered breathing in children first, primarily obesity, before putting them under the knife.

Antibiotics don't work for sinusitis
This study from the Lancet received some press in the media. This was a meta-analysis, a technique where multiple studies are examined together, looking whether common signs and symptoms in patients that have rhinosinusitis could be used by physicians to predict which patients would benefit from antibiotics. The study showed that none of the typical predictors (fever, green nasal discharge, facial pain) predicted which patients got any better from antibiotics. Though this may seem surprising, it shouldn't. Most cases of sinusitis are caused by viruses, which don't respond to antibiotics. In addition to not working, antibiotics cause side effects, cost money, and lead to resistant super-bugs like MRSA that we are starting to see cause serious infections in the community.

Vitamin E and C do not reduce dementia risk
As reported in Reuters and other sources, this study from the Journal of the American Geriatrics Society looked at almost 3,000 seniors without signs of dementia initially and found that the use of supplemental vitamin E and C, alone or in combination, did not reduce risk of Alzheimer's disease or overall dementia after more than 5.5 years.
I am not anti-supplement. Certain supplements (Vitamin D, Calcium) are important and are likely necessary in many patients. However, this does not hold true for many of the supplements and herbal medications that patients take on a regular basis. I have blogged about before, studies have shown that beta carotene, vitamin A, and vitamin E may even increase your risk of death.

Sunday, March 9, 2008

Eli Lilly terminates inhaled insulin program

As reported in the Wall Street Journal, and other sources, Eli Lilly made the decision to terminate their development program for inhaled insulin. This follows two other companies who have taken similar steps, NovoNordisk a few weeks ago, and Pfizer's dropping Exubera after it had been out on the market (which I put on my "worst" list for 2007). Only one small company (Mankind in California) is left trying to bring inhaled insulin to market.
When Pfizer pulled Exubera, it did so for financial reasons; since not enough prescriptions had been written. Lilly, who was finishing up studies to get their drug approved, stopped the drug not for safety reasons, but similar concerns that their drug would not do well. Specifically,

this decision is not a result of any observations during AIR Insulin trials relating to the safety of the product, but rather was a result of increasing uncertainties in the regulatory environment, and a thorough evaluation of the evolving commercial and clinical potential of the product compared to existing medical therapies.

The key word here is "regulatory environment," which basically means that they were concerned whether or not the FDA would approve the drug, or if approved would be restricted in the way they were able to promote it. If they state that there were no safety concerns, then why would they think the FDA might not approve their drug easily? How might they be restricted in their promotion?

Here's the issue: Vioxx was a great example of how we need to look very carefully at safety before, and more importantly after a drug has been approved. The problem may be that we have gone too far. The political and heightened media scrutiny of the FDA and drug companies may be in part to blame for a needed drug not coming to market. As I have posted recently, the FDA now plans on releasing safety concerns to the public earlier and more frequently, even if they are not sure that a safety problem truly exists. Remember all the media attention regarding Avandia? Do you remember the headlines when the FDA concluded "there is not enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes treatments?" (You probably don't, because there really were no head lines-good news doesn't really sell). I had also posted about the NIH stopping the intensive treatment in the ACCORD study for diabetes. Though the study showed an increased risk of death in the intense treatment arm, both groups had a death rate that was much lower than usual, and the difference was 3 deaths per 1000 patients. I wonder if the the ACCORD study would have been discontinued prior to events like Avandia and Vioxx?

Pfizer's Exubera failed for three reasons: 1) it first targeted endocrinologists instead of primary care physicians who were the best candidates to prescribe the medication 2) the device was significantly larger then most inhaled products and 3) they were pressured by the FDA not to minimize lung safety issues, when 2 years worth of data showed non clinically meaningful lung problems. Had that 3rd barrier not been there, and had Pfizer launched the product differently, Exubera might have been a best selling drug. I had many patients very upset when Pfizer pulled the plug.

Type 2 diabetes is a growing epidemic in our country. Of the 20 million or so patients estimated to have type 2 diabetes, only about 12 million received treatment, and of those only slightly more than one third have their sugars under good control. A study showed that for patients on more than one diabetes pill, doctors often wait up to 3 years with sugars very poorly controlled before adding insulin. Of those patients not controlled on more than one drug, fewer than 20% got the insulin they needed. Why? Because patients don't want to be on insulin. One thing has to do with the fact that for many patients, taking insulin means they have a serious disease, and not just something they need to take pills for. Secondly, is the obvious injection part which inhaled insulin overcame. Thus, inhaled insulin (even in a large inhaler) was a major breakthrough, that we will never likely see in the near future.

It is very easy to criticize the pharmaceutical industry for making too much money advertising expensive products to doctors and patients. Similarly, it is very easy to fault the companies every time an undiscovered side effect is reported. The media has done an excellent job at this. However, it is harder to admit to that a profitable pharmaceutical industry is necessary in order to see innovative products. In addition, if the FDA (due to its intense recent scrutiny) is going to be overly cautious about every side effect, companies may choose not to develop products which huge potential gain for many because of some minimal side effects to a few.

Wednesday, March 5, 2008

Pills, Pills, Pills

A few studies and media stories that have come out recently may helpt to shed some light on medications and how we use them.

First, the Wall Street Journal , MSNBC and others have reported on an interesting study from MIT published in this week's JAMA that showed a placebo pill was more effective when patients thought it cost more money. Briefly, 82 healthy volunteers were given a placebo pill that they were told was for pain relief. Half were told the pill cost $2.50 and the other half was told the cost was 10 cents. Subjects were (safely) given painful shocks. 85.4% of the participants experienced pain reduction after taking the expensive pill compared to 61.0% of patients taking the cheaper placebo.

Second, and interesting essay in the NY times by Dr. Abigail Zuger on Dr. Jarvik's role in promoting Lipitor ( the story that won't seem to go away) and pharmaceutical marketing in general.

Finally, several sources (Med News Today , Washington Post ) reported on a study that analyzed studies submitted to the FDA on anti-depressants like Prozac, Paxil and Effexor. To determine if these drugs improve depression, studies use a survey called the Hamilton Rating Scale for Depression (HRSD). The HRSD score ranges from 0 to 54. Though on average the medications were better than placebo, with a mean improvement of 9.60 points on the HRSD in the drug groups and 7.80 in the placebo groups, the 1.80 difference in HRSD score while statistically significant, did not reach what is considered to be a real and clinically meaningful change of 3 points, which was found only in the severely depressed patients.

Taken together, these three studies reveal a lot about how medications work and how marketing and cost may even affect medicines ability to work.

The placebo effect is a true phenomenon, and may have about a 30% benefit. Though the MIT study is interesting, it should be noted that both placebos had a substantial improvement. Yet, what we think about a drug may have a huge impact on whether or not it actually works on us. Cost of a drug implies that it is newer, and likely more effective. Thus, if we think we are taking the newest, most expensive drug, it may actually work better. This could imply that having Dr. Jarvik tell us that Lipitor works, may in fact not actually be such a bad thing? (more on that in a moment)

Antibiotics are another example of this. KevinMD's site has a great post from Dr. Rob on the myths of antibiotics. In my experience, patients often want an antibiotic because they think that they have more than just a cold, and that antibiotics are somehow "stronger." I have heard patients say that the only thing that will work on their cold is an antibiotic. Is this also the placebo effect? Though many antibiotics are now generic, use of antibiotics as a placebo is ill advised because of the development of resistant bacteria, which have now become a substantial problem in the community.

Trials submitted to the FDA use placebos to account for this affect. The meta-analysis on anti-depressants was interesting, but one should not infer that we should stop using anti-depressants in depression because the difference between placebo and treatment was on average almost 2 and not 3 points. With the additional real placebo benefit, patients on actual antidepressants had almost a 10 point reduction in HRSD, which is significant and meaningful. We could just start prescribing placebo pills for depressed patients, but I doubt this will ever be considered medically ethical.

Going back to drug advertising, one of my favorite studies on this subject was published in JAMA. Trained actors were sent to doctors offices, half given the role of someone with true depression where a drug would be indicated and the other half given the role of someone who was just sad, but not needing a medication. Both groups were further divided into two groups-half said they saw and ad on television for a drug and they wanted it, the other half did not. Not suprisigly, the patients who mentioned the TV ad were more likely to get the drug, regardless of their condition. What this means is that the TV ad led to increased appropriate prescribing in patients that really needed the drug, but also led to unnecessary prescribing for patients that didn't need the drug. Thus, though there is no question that drug ads on TV increases sales (and cost), the risks and benefits of TV drugs ads are not as clear cut.

Thinking a drug will work is clearly important, and industry can either enhance this effect for patient benefit, or manipulate it for increased profits. Physicians can take advantage of the placebo effect by reinforcing the efficacy of recommended medications with their patients, but must be cautious not to prescribe unnecessary medication just becaue a patient wants something.

Saturday, March 1, 2008

More FDA warnings should not be cause for worry.

As reported the other day in the Wall Street Journal, in response to public concern about the safety of medications, the FDA plans to release information to health care professionals and the public earlier and more frequently than in the past. Previously, the FDA would wait until there was clear confirmation that adverse effects reported from drugs were actually true, and caused by that drug. However, due to increasing scrutiny and concern over drugs like Vioxx, the FDA will release information on reported events even earlier.

This sounds like a good thing, and it is. However, my concern has to do with the way the media reports such announcements, patients reactions to this, and sometimes confusing process and terminology of what an FDA warning actually means.

As reported in the WSJ, FDA Commissioner Andrew von Eschenbach stated, "I feel strongly it's important for us to communicate early, but in communicating early we are acting with a much smaller degree of certainty." Translation:many of these "warnings" or "alerts" are meant to be informative, and don't necessarily mean cause for alarm or even that the reported problem is actually true.

Bottom Line: Increasing public awareness about potential adverse reactions is a good thing, but please do not be alarmed every time you hear on the news that there is a new warning about a particular drug.

For those who are interested: (Sorry for such a long post, but this is a complex issue.) For a drug to be approved by the FDA, the company that makes the drug has to prove that it is both safe and effective. Though companies will submit data on thousands of patients taking their drug : 1) the patients enrolled in these studies are usually carefully selected and may not be representative of the entire population and 2) it may takes tens to hundreds of thousands of patients to see an uncommon (but sometimes serious) adverse event.

The current process is that once a drug is approved, two ways to ensure safety are 1) the company commits to doing studies on the drug after its release to the public and 2) patients, physicians and others can report any adverse events to the FDA, who will keep tabs on these regularly, looking for a signal of a problem. The problem is that not all companies have fulfilled their commitments to these post-marketing studies and reporting of adverse events is voluntary.

Chantix, Pfizer's drug for smoking cessation is a great example.

Smoking is the single leading preventable cause of death in the United States. Current guidelines recommedn that every patient interested in quitting smoking be offered some medication (patch, gum, pills) because these agents double the chance at successfully quitting. Chantix is currently the most effective agent for quitting smoking with good studies to back this up. In the initial studies presented to the FDA, with the exception of nausea (about 30% of patients get nausea, though it is usually mild and usually goes away), the side effect profile with Chantix was pretty darn good.

However, the FDA starting getting reports about patients with previous mental health conditions having serious mood and behavior disturbances after starting Chantix. On November 20th, 2007 the FDA released an "early communication" about this, followed by a public health advisory on February 1st, 2008 that "updated the Chantix prescribing information to include warnings about the possibility of severe changes in mood and behavior in patients taking Chantix" as well as an update to the product's label.

That's when the media stories started to run wild. CBS news and other sources reported that Chantix may have lead to a rock musician's suicide. MSNBC stated that "Anti-smoking drug may be tied to suicide risks" which was tame compared to other heavily googled news sites on the web that claimed "Pfizer Anti-Smoking Drug Chantix Worries FDA"

How could such a useful drugs with a pretty good safety profile be found to cause these problems? Some of the initial studies on Chantix compared it the only other drug approved for smoking cessation, bupropion (Chantix was found to be significantly better). However, bupropion is also used for depression. Because of this, people with mental health disorders were excluded from these intial studies. From a research standpoint, this was appropriate. However, persons with mental health disorders are about twice as likely to smoke, and disproportionately represent the population of current smokers. In addition, patients with mental health disorders may use nicotine to treat their illness. Finally, withdrawal from nicotine can itself exacerbate mental health disorders. So was it Chantix that caused these problems, or just that patients with mental health issues (who had not previously been studied) got worse after they stopped smoking? Currently, this is unclear.

Therefore, FDA's repsonse was thus appropriate. Within the label, doctors are now warned about worsening mood and behavior for patients with previous mental health conditions taking Chantix. The FDA added this to the drugs label as a "warning." This does not mean that Chantix is necessarily dangerous or problematic, and thus the media hype about the "dangers" of Chantix was not only unwarranted, but may have been harmful itself since patients who may have been using Chantix stopped taking the drug unnecessarily.

Another issue is the terminology used by the FDA may be confusing to the public (and even some physicians). The information about a drug's use, side effects, interactions, etc. is in a document called the label. On the FDA's web site (though difficult to find) is a Guidance document (posted in draft form) which points out there are muliple levels of warnings in a drug's label.

Some definitions:

Adverse Reaction is "an undesirable effect, reasonably associated with the use of a drug." This is not necessarily soemthing bad or serious.

Adverse Event is "any untoward medical event associated with the use of a drug...whether or not considered drug-related."

A Serious Adverse Reaction is something (obviously) serious, that may have lead to death, hospitalization, disability or birth defect.

Based on the type of reaction or event, this can come under several places in the product's label.

WARNINGS AND PRECAUTIONS: Under this section, these recommendations are about adverse reactions, which may not necessarily be serious, but thought to be clinically significant. Warnings also and usually contain serious adverse reactions as well as drug interactions.

CONTRAINDICATIONS: This means that you shouldn't use this medications in these particular circumstances.


This category is the most confusing and media hyped. First, there is no such thing as a "Black Box," which is a term created by the media. Boxed warnings are warning that are thought to be important enough to go at the very top of the label and are highlighted by being surrouned by a box. A product can get a boxed warning for three reasons.

  • "an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using a drug"

  • A serious adverse reaction that can be prevented by appropriate (i.e. avoiding drugs that interact).

  • The FDA approved the drug with restrictions.

A boxed warning an appropriate caution to health care providers, but again does not necessarily mean that the drug is unsafe to use. There are many drugs (metformin for diabetes for example) that are commonly used safely and effectively that have a boxed warning. For Chantix, the new information about potential adverse events came under the heading of "warnings."