Postinfectious Cough

I am not a huge baseball fan to begin with, and when I am, I route for the Nationals.  Thus, I pay little attention to the New York Yankees, and was not aware that Yankee player Mark Teixeira had been suffering with a cough for the past month until it the story from the New York Times came through one of my Twitter feeds. According to the story:
"Mark Teixeira had a battery of tests performed Wednesday to determine the nature of his violent and persistent cough, and he received good news. Teixeira, who has been wracked by the cough for about a month, said he was found to have nothing more serious than severe congestion in his bronchial passageways." 
Mr. Teixeira was prescribed prednisone (not something I would recommend for this) and is expected to recover soon. In addition, the doctors at New York-Presbyterian/Columbia hospital in Manhattan performed a CT scan, a lung function tests, blood tests and cultures during their work up (though I am sure the Yankees can afford this). The Times does not mention the diagnosis other than to say that the baseball player had "severe inflammation in my bronchial passageways."

I blog about this because this is one of the most common things I see in the primary care setting, it is often misunderstood and therefore misdiagnosed, it is very easily treated and there is virtually no research on this disease.

Mr. Teixeira likely has what is known as postinfectious cough. Here's the typical patient presentation:
Young healthy patient gets a typical upper respiratory tract infection (URI): cough and congestion, headache, feels ill and low grade fever. URI resolves in a matter of days, but there is a persistent cough that is getting worse, and won't go away.  Cough is usually worse at night, and the patient can't exercise because it makes them cough. On occasion the cough is so bad that the patient is winded easily and sometimes the patient thinks they may be wheezing, though they have no history of asthma.

According to the American College of Chest Physician which published evidence-based clinical practice guidelines back in 2008, the diagnosis of post infectious cough should be considered when a patient complains of cough that has been present following symptoms of an acute respiratory infection for at least 3 weeks,but not more than 8 weeks.  And while the cause of the postinfectious cough is not known, it has been thought to be due to the extensive damage of cells lining the lung and widespread airway iinflammation of the upper and/or lower airways. The good news is that this usually goes away by itself, the bad news is that it can take weeks or even months, and can be quite disruptive to patients lives; desk jockeys and baseball players alike.

To me one of the most incredible things about this illness is the lack of data on effective treatments. The ACCP review cited above did an extensive review of the literature and found very few studies that looked which treatments worked best. Given the lack of data, here is my take on the appropriate diagnosis and treatment:

Diagnosis can be made without an extensive workup when the clinical presentation is consistent with that described above and there are no other complicating factors that would indicate other possibilities. A chest X-ray may be all that is necessary to rule out any underlying severe disease and is reasonable in a patient who has been coughing for more than two weeks.

Since symptoms are caused primarily by inflammation and hyperresponsiveness/bronchoconstriction in the lungs (which is what we see in asthma), then treatment is likely best with something that treats both inflammation and bronchoconstriction in the lungs, such as an inhaled corticosteroid/long-acting beta agonist like Advair (which is commonly used in asthma).  Of note, Advair (or other ICS/LABA combinations) have not been approved by the FDA for the treatment postinfectious cough and there is no data on the use of ICS/LABA's for the treatment of postinfectious cough.  However, this is a common sense approach to the problem based on what we know about the cause, and from clinical experience I can tell you this approach works remarkably well.  Use of Advair for postinfectious cough may be the single most common off-label use of any prescription product.
There are two additional important points.  First, since inflammation can persist for weeks, it is important that Advair be used for at least 4 weeks.  If stopped too soon, before inflammation has completely resolved, symptoms may return.  This is very important, because primary care physicians who decide to use ICS/LABA inhalers for postinfectious cough may give patients a medication sample rather than a prescription.  Though the drug companies that make these products used to make samples with a month's supply of medication, most inhaler samples today have only 1-2 weeks of therapy.  Secondly, if symptoms have resolved and the patient has taken the inhaler for 4-6 weeks, the patient can safely stop the inhaler.  If symptoms return, the patient should be brought back for pulmonary function testing as this may be a new presentation of asthma.

Good Bye Primatene Mist

As reported today by the Washington Post, Primatene Mist’s days are numbered. The FDA announced today that "the only over-the-counter asthma inhaler sold in the United States will no longer be available next year as part of an international agreement to stop the use of substances that damage the environment."

This is because, similar to the old albuterol meter dose inhalers, Primatene Mist uses a CFC as a propellant which is harmful to the environment. I blogged about this previously (see FDA Announces End for CFC-Propelled Inhalers Asthma inhalers and More on Asthma Inhalers ).

However, the loss of Primatene Mist is a good thing in my opinion. Primatene Mist is epinephrine. It is a bronchodilator, which is why it relieves the symptoms of asthma. However, it is quite dangerous, especially without a prescription. First, it is not just a beta 2 agonist like albuterol which works almost exclusively on beta receptors in the lungs. It also aftects beta 1 receptors in the heart and alpha receptors in the blood vessels. The primary use of epinephrine is medicine today is to give it to patients who are a risk of immediate death in order to restart their hearts. In addition, having any bronchodilator, even albuterol, over the counter, is a bad thing. We know that increased albuterol use is associated with increased ER visits, hospitalizations and even death. But at least we can monitor albuterol use, because it must be prescribed by a physician. We have no way of knowing if a patient is taking too much Primatene mist until they are dead.

Under a physician's supervision, with a proper asthma plan and additional chronic maintenance medications for asthma, such as inhaled corticosteroids, bronchodilators can be used safely and effectively. However, over-use of these medications especially in the absence of inhaled corticosteroids is dangerous. This is why I never write an albuterol prescription with any refills. If your asthma is well controlled, one albuterol inhaler should last you a year and you shouldn't need refills. If you are refilling the albuterol more than one time in a year, by the NIH's criteria, your asthma is not under control and you may need to change to a stronger daily medication (for example, switch from Singulair to an inhaled corticosteroid or ICS, or switch from an ICS to an ICS/LABA combination).

For those patients without prescription insurance who relied on the relatively low cost of OTC Primatene mist, be advised the GSK makes a sample size of Ventolin HFA (60 inhalations) that is only $9 out of pocket (regardless of insurance) at most major retail pharmacies. This will of course require a doctor's prescrition, but I believe that is a good thing for the reasons stated above.

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.

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.

FDA Announces End for CFC-Propelled Inhalers

As reported in Med Page Today, the FDA Announces End for CFC-Propelled Inhalers. Of the seven inhalers with deadlines for removal, only three are still being made:

Flunisolide (Aerobid Inhaler System) on June 30, 2011
Albuterol and ipratropium combination (Combivent Inhalation Aerosol) on Dec. 31, 2013
Pirbuterol (Maxair Autohaler) on Dec. 31, 2013

The reason for this is because CFC's are harmful for the environment, and the newer inahlers have to be replaced with a different, more environmentally friendly propellant called hydroflouroalkane or HFA. I have blogged about this previosuly (please see Asthma inhalers and More on Asthma Inhalers ).

According to the FDA, "patients using the inhalers scheduled to be phased out should talk to their health care professional about switching to one of several alternative treatments currently available. Until then, patients should continue using their current inhaler medication."

What you should do:
1. Albuterol If you are taking albuterol, please see my earlier posts. I still have patients that have their very old albuterol canisters, which are probably no longer effective. An important thing to know is that there is no longer any generic albuterol. More importanly, if your physician writes a prescription for albuterol, the pharmacist will likely give you ProAir, which may or may not be what your insurance prefers and/or what is least expensive for you. This is because many of the chain pharmacies are getting a kick back from the makers of ProAir. Make sure your provider writes for the correct inhaler. All things being equal (same co-pay for patients), I recommend Ventolin HFA (because it is the only one with a dose counter) or Xopenex HFA, because of diminished side effects. NEW INFORMATION: GSK, makers of Ventolin HFA sell a $9 inhaler, regardless of your insurance. Though the inhaler has fewer puffs in it, if you are using your inhaler that frequently, then your asthma is not under good control, and you should be on a different controller medication. Ask your doctor for Ventolin HFA 60 (they have to write the 60 part).

2. Maxair- Some patients love this drug, but it's going away. Before January 2014, get another albuterol. See above and previous posts for advice.

3. Aerobid- I didn't even realize they still made this medication. It is no more effective then other similar medications, probably less effective, possibly more side effects, and it tastes nasty. If you are on this medication, switch ASAP to another inhaled steroid. Good alternatives include Flovent, Pulmicort, Asmanex, and Alvesco.

4. Combivent- This will likely affect patients the most, since few patients are on Maxair or Aerobid, and there are far more COPD patients than asthmatics. It is very likely that before January, 2014, the makers of Combivent with come out with a Combivent HFA. However, there are reasons to consider switching now. Please see older posts Good News for COPD , Bad news for COPD: Why this meta-analysis should be believed (and the Avandia one should not) , and UPLIFTing News for COPD

Briefly, a few studies have come out which make me very concerned about using Combivent. One study published in the Annals of Internal Medicine studied a VA population and found that patients taking ipratropium had significantly higher death rate of about 11%. A second study was a meta-analysis published in JAMA that analysed date from 14,783 patients with COPD and found that patients taking either ipratropium or tiotropium (Spiriva) or both had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). Though combined, these studies might cause safety concerns with the entire class of anti-cholinergic inhalers, the UPLIFT trial, a long-term, large randomized controlled trial (4 years, almost 6000 patients) which unfortunately failed to show that Spiriva could decrease that rate of lung function decline, did show about 10% relatively fewer deaths. Thus, though anti-cholinergic medicines may cause some harm, it appears that this is likely mainly for the short acting ipratropium and not for the long acting tiotropium. I would therefore recommend that COPD patients talk to their doctors about stopping their Combivent now and switch to a different controller medication (Advair, Symbicort, Spiriva) and/or switch to albuterol alone as a rescure medication.

FDA Blows it on LABA Safety

The FDA just killed a few asthmatics!



I have blogged extensively regarding LABA safety (see The Lowdown on LABA's , Good News for Asthma Patients , Asthma Medication: Calling Out the Safey Advocates and Dear FDA, Remove the Boxed Warning from Advair and Symbicort )


As reported today in the Wall Street Journal and MSNBC (so far), the FDA announced today that is was changing the labelling on products containing long acting beta2 agonists, or LABA's. One of the changes was recommending 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."


Not only did the FDA get it wrong regarding their interpretation of the data, but they did two surprising things. First, in addition to simply saying what is safe and what is not (their job), they made treatment recommendations (not their job); recommedations that are actually not consistent with national guidelines. Secondly, their recommendations are based on absolutely no data! In fact, the limited data available would suggest that their approach may not be a good idea. Finally, taken together with the fact some of the headlines will scare patients and cause them to simply stop taking their medications, patient will undoubtedbly suffer. Ironically, the FDA's reaction to the few potential harmful effects that they are worried about regarding LABA's have led to actions that will likely cause substantially more harm to patients.



LABA's ARE SAFE WHEN TAKEN WITH INHALED STEROIDS

At face value, the LABA safety issue should not be an issue. Asthma deaths climbed steadily into the mid 90's, unlit about 1996/1997 when the rate of asthma deaths declined for the next decade and have remained stable over the past few years at about 4000 death per year. LABA's were introduced at exactly the time that asthma deaths declined. Though one can not prove that the decline in asthma death rates are due to the use of LABA's, it certainly can not be the case that LABA's cause asthma deaths.

One of the FDA"s recommendations did make sense: LABA's should not be taken alone and only used with an inhaled corticosteroid or ICS. The entire LABA controversy centers around the SMART study published back in 2006. SMART was a very large (over 23,00 patients) study done by GSK, the makers of the LABA salmeterol, looking at its safety. The problem was that it didn't study only asthmatics taking ICS, but asthmatics taking any medication. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including asthma death. Because of these findings, the FDA not only applied a boxed warning to salmeterol, but all LABAs and products containing LABAs. Advair, one of the most common asthma controller medications contains the LABA salmeterol and an ICS. The data from the SMART study was very clear that most of the problems came from asthmatics taking LABA's alone, and that there were no increased problems (regardless of ethnicity) when using a LABA with and ICS. In fact, no one taking Advair or Symbicort equivalents in the SMART study died! However, this was not enough for the FDA or critics to give ICS plus LABA products a pass on the boxed warning. The only way to prove to the FDA (and some critics) that ICS + LABA's are safe would be to do another SMART like trial on patients taking ICS alone or ICS+LABA. The problem is that this trial would likely require at least 250,000 patients (because events are so rare), and no drug company is going to fund that study. In an effort to get more data, several meta-analysis were done. GSK's own meta-analysis which looked at ICS + salmeterol compared to ICS alone showed that ICS + LABA actually decreases the risk for severe exacerbations, and did not increase the risk for asthma-related hospitalizations or asthma-related deaths. The FDA did their own meta-analysis (most of the data coming from SMART) which seemed to show the same thing. In fact, regarding Advair, the committee voted 27 to 0 that Advair was safe. Thus, it is quite surprising that the FDA would go in a different direction that what their advisor committee was suggesting.



THE FDA'S RECOMMENDATIONS TO STEP DOWN TO ICS AFTER CONTROLLED ON ICS + LABA ARE NOT EVIDENCE BASED OR CONSISTENT WITH NATIONAL GUIDELINES

The most recent asthma guidelines were published in November 2007. There is a strong focus on asthma control. The guidelines say that the focus of asthma care should be control, and that if control is not achieved, therapy must be stepped up, because poorly controlled asthma puts patients at risk for bad outcomes, such as hospitalization and death. In a recent study, we showed that that majority of patients in the primary care setting had poorly controlled asthma, and that one out of every three patients seen in primary care was using a rescue albuterol inhaler every day. The guidelines suggest that once asthma control is achieved that providers can continue therapy or CONSIDER stepping down. The guidelines are very specific that step down therapy should be done carefully, as it might risk worsening asthma. In addition, when talking about step down therapy, most of the discussion in the guidelines is about reducing the dose of the ICS, and not discontinuing the LABA (supported by data published in the New England Journal) Thus, by mandating that patients who are well controlled on ICS+LABA step down to an ICS alone, the FDA is both dictating treatment, which is not really their role, and in doing so, going against well accepted guidelines developed by an expert panel from the NIH! More importantly, there is extremely limited data on which route is best in a stable asthmatic patient: continuing ICS + LABA or stepping down to ICS alone. One study in the US of 647 patients controlled on Advair did worse when stepped down to ICS alone. 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. There are only a couple more studies like this done, all showing the same thing: the FDA's recommendations are ill advised.



PATIENTS WILL STOP THEIR ADVAIR, AND THIS WILL LEAD TO EXACERBATIONS

There is very compelling data that shows when asthmatics stop their controller medications, that bad things happen, including ER visits, hospitalizations, and even death. First, though data is limited, there are studies which suggest that patients taking ICS + LABA are more likely to refill their prescriptions than those taking ICS inhalers alone. In fact, in one managed care study, the adherence to ICS + LABA in one inhaler (i.e Advair) was double that of patients taking the ICS alone. In addition, prescriptions for the rescue medication albuterol, as sign of worsening asthma, was higher in those patients taking an ICS alone. Thus, it is possible that patients who step down from and ICS + LABA to an ICS alone may not be as adherent to their controller asthma medication, and could get sicker. Finally, many physicians will attest to the fact that when there is bad press about a medicine, patients will stop, sometimes without discussing it with their doctor. We looked at patients in our practice after the Avandia scare in 2007, and found that many stopped taking the medication without discussing this with one of our physicians. Anecdotally, when the SMART data was first released and drew media attention, several physicians from various parts of the country told me they noticed increased ER visits due to asthma. This is why I am certain that the FDA decision today will cause patient harm.

Sick About Singulair

The New York Times' business section recently reported that despite a second-quarter earnings fall, hurt by lower sales of its cholesterol drugs (specifically Vytorin, see my posts on why you should no longer use this product), Merck actually beat profit forecasts due to good sales of its asthma drug Singulair. Singulair's quarterly sales jumped 16 percent to $1.3 billion. That's a lot of money! Indeed, based on pharmacy data (via drugtopics.com, thanks again Mr. Medsaver for this great resource), Singualir was the 4th most commonly prescribed drug in 2008 at a close to 26 million prescriptions! Moreover, a recent report from the WSJ Health Blog states that Merk is looking to put Singualir over the counter.



I have no ill will towards Merk. It is an American company that has come up with some products that I find beneficial for patients including Fosamax (which is now generic) and Januvia, and they are the makers of two important vaccines: Gardisil and Zostavax. However, I am concerned about high sales of the asthma drug Singulair, because national guidelines state it should not be used as a first line therapy for asthma.



Facts about asthma



According to the American Lung association, in 2007, it was estimated that 22.9 million Americans currently have asthma. Of these, 12.3 million Americans (3.8 million children under 18) had an asthma attack. In 2005, there were 3,884 deaths attributed to asthma. During 2006, 444,000 hospitalizations and close to 1.7 million emergency room visits were attributed to asthma.



In 2007, the NIH released updated guidelines about asthma. Regarding treatment, the guidelines suggest that all asthmatics with persistent asthma (symptoms or rescue medication use more than twice a week) be initiated on inhaled corticosteroids (ICS). ICS's are considered first line treatment for all asthmatics, from babies to children to adults and to the elderly. The reason is based on solid evidence that these agents work the best in improving lung function and decreasing symptoms. Singulair is listed as an alternative agent. Singulair is an anti-leukotriene. Leukotrienes, like histamines, are substances released in an allergic response that cause the airways to tighten up. Thus, Singulair works in the same way that antihistamines work: by treating the symptoms. ICS's work by blocking inflammation which is what causes the release of leukotrienes in the first place. Singulair is not anti-inflammatory, ICS's are. Singulair treats the symptoms, whereas ICS's treat the problem. This is why study after study proves that ICS's are superior to Singulair, and why guidelines place ICS's as first line treatment and Singulair as alternative.





Does Singulair work?
Of course Singulair works. In order for a drug to be approved by the FDA, the drug company has to show that its product is efficacious. The problem is that it has to show that it is efficacious compared to placebo. Thus, Singulair works better than a sugar pill. However, compared to any other asthma medication, it is not as good. Even when added on to an ICS, it is not as good as other add ons, such as long acting beta agonists (LABA's).



Why do physicians prescribe so much Singulair when is not what the guidelines recommend?

This is an extremely important question. Some may chalk it up to drug company marketing. However, all the ICS and ICS/LABA making companies due their job marketing their product as well. I think the main reason has to do with fear of ICS's. Corticosteroids are different than the kind of steroids athletes take. However, they are not without side effects. Earlier studies on older medications showed some growth delay in children, which is why pediatricians may be so reluctant to use ICS's. However, more recent studies showed that for the newer agents, long term use with mild to moderate doses did NOT cause growth delay. In 2002, the NIH reviewed all the literature and determined that at low to medium doses of ICS's, there are NO SIGNIFICANT SIDE EFFECTS. This is when ICS's became considered first line therapy for ALL asthmatics.

The other issue is the convenience factor of a pill vs. an inhaler. Inhaler use is clearly not as easy as taking a pill (Singulair comes chewable for children).

The thought is probably, "it's a once a day pill that might help my patient, and probably won't hurt them, so why not give it try?" The problem with this approach, is the failure to consider the risks of uncontrolled asthma. Uncontrolled asthma leads to ER visits, hospitalizations, and possible even death. Asthma is a serious disease. For patients who have persistent asthma, following the guideline recommendations of ICS's as first line agents is the right thing to do.

What about allergies?

Singulair is also indicated for allergic rhinitis or allergies. As above, like histamine, leukotrienes play a role in allergic rhinitis, and this is why Singulair is used. I have posted about Singulair and allergic rhinitis previously. Basically, there are several treatments for nasal allergies:Non-sedating antihistamines (Claritin, Zyrtec, Allegra), Leukotriene modifiers (Singulair), inhlaed nasal steroids (Flonase or fluticasone, Rhinocort, Nasacort, Veramyst) and inhaled nasal antihistamines (Astepro). Muliple studies that show that fluticasone (Flonase) is better than Singulair, better than Claritin, and several studies that show that the combination of Singulair and Claritin is not better than either agent alone. However, in one study, though the combination of Singulair and Claritin was better than either agent alone, the individual agents were no better than placebo. An excellent review by Dr. Robert Nathan showed that "leukotriene receptor antagonists (Singulair) are sometimes more effective than placebo, are no more effective than nonsedating antihistamines (Claritin) , and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis." Finally, a recent guideline from World Health Organization suggests that for patients with mild, intermittent allergic rhinitis; treatment with non-sedating antihistamines and leukotriene modifiers were both acceptable forms of treatment, but patients with more chronic or bothersome symptoms, inhaled nasal steroids should be used.

Some would argue that having both allergies and asthma together would be a reason to take Singulair. There is no question that treating allergic rhinitis may help with asthma symptoms. However, the killing two birds in one stone approach simply hasn't been proven to be the case. If you have allergic rhinitis that makes your asthma worse, you should take the most effective agent, which is inhaled nasal steroids.





What if I am taking Singulair for asthma?

Singulair has been proven more effective than placebo, and in some individuals controls their asthma and allergies. However, a recent internet survey revealed that about 55% of asthmatics have uncontrolled asthma, and many of them are on regular medications. Asthma control is the key, according to the new NIH guidelines. If your asthma is well controlled on Singulair, then it is probably OK to take. However, there is a theoretical risk that by taking Singulair (treating the symptoms without treating the underlying inflammation), that though you feel well now, your lung function will be worsening over time. More importantly, if you are taking Singulair and your asthma is not well controlled, then you should definitely switch to at least an inhaled corticosteroid, or possibly an agent combining an ICS with a long acting brochodilator (LABA) such as Advair or Symbicort. There are many ways to determine asthma control, including how much rescue medications you are taking and how asthma affects your daily life. The easiest way to determine your asthma control is by taking the Asthma Control Test