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.
Showing posts with label symbicort. Show all posts
Showing posts with label symbicort. Show all posts
Monday, September 20, 2010
Tuesday, June 15, 2010
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.
"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.
Thursday, April 8, 2010
FDA too focused on risks compared to benefits when approving drugs
In my opinion, the pendulum has swung to far in the safety direction when it comes to approving new drugs. Over a decade ago, the reverse was true and medications like Vioxx and Rezulin were approved and prescribed too quickly without either additional studies required before approval or closer follow up after approval. Though a more vigillant approach to safety was certainly needed, now there are many drugs that may never get approval because it appears that the FDA is concerned about virtually any risk at all.
Today, as reported best by Medpage in Panel Votes Against New PDE4 Inhibitor for COPD, despite prior discussions in favor of the drug, the FDA decided not to approve roflumilast (Daxas), a phosphodiesterase 4 (PDE4) inhibitor, for treatment of chronic obstructive pulmonary disease (COPD). Now, I will admit after seeing some of this data, that I was not overly impressed with Daxas. It would never be my "go to" drug for COPD, because we have so many better options such as inhaled corticosteroid/LABA combinations (Advair, Symbicort) and long acting anti-cholinergic agents (Spriva). However, there are still many patients with COPD who take both drugs as well as additional short acting inhalers, and are quite symptomatic. In addition, prior to either of these medications being available, one of the primary treatments for COPD was theophyline, one of the original PDE inhibitors. It had a far worse side effect profile than Daxas (seizures, blood levels needing to be monitored), but was the mainstay of therapy. In fact, there are many doctors still prescribing theophyline today for their COPD; mainly in those patients who can't take or are still symptomatic on the aforementioned inhalers.
Looking at the Daxas data, roflumilast resulted in a significantly greater change in prebronchodilator FEV1, improving it by 48 mL over the course of the study (P<0.0001). This amount of improvement would be minimal for a healthy person or even an asthmatic, but for a patient with COPD, this could be the difference of being able to walk up the stairs or having to live on the first floor. In addition, the number needed to treat to prevent once exacerbation was significant, between 3 and 5. In other words, even though this was not the best medication in the world for COPD, it was certainly beneficial, and would have an important role for patients not well controlled on standard therapy.
Today, as reported best by Medpage in Panel Votes Against New PDE4 Inhibitor for COPD, despite prior discussions in favor of the drug, the FDA decided not to approve roflumilast (Daxas), a phosphodiesterase 4 (PDE4) inhibitor, for treatment of chronic obstructive pulmonary disease (COPD). Now, I will admit after seeing some of this data, that I was not overly impressed with Daxas. It would never be my "go to" drug for COPD, because we have so many better options such as inhaled corticosteroid/LABA combinations (Advair, Symbicort) and long acting anti-cholinergic agents (Spriva). However, there are still many patients with COPD who take both drugs as well as additional short acting inhalers, and are quite symptomatic. In addition, prior to either of these medications being available, one of the primary treatments for COPD was theophyline, one of the original PDE inhibitors. It had a far worse side effect profile than Daxas (seizures, blood levels needing to be monitored), but was the mainstay of therapy. In fact, there are many doctors still prescribing theophyline today for their COPD; mainly in those patients who can't take or are still symptomatic on the aforementioned inhalers.
Looking at the Daxas data, roflumilast resulted in a significantly greater change in prebronchodilator FEV1, improving it by 48 mL over the course of the study (P<0.0001). This amount of improvement would be minimal for a healthy person or even an asthmatic, but for a patient with COPD, this could be the difference of being able to walk up the stairs or having to live on the first floor. In addition, the number needed to treat to prevent once exacerbation was significant, between 3 and 5. In other words, even though this was not the best medication in the world for COPD, it was certainly beneficial, and would have an important role for patients not well controlled on standard therapy.
Safety concerns were certainly real. A total of 218 cancer/tumor events were reported in 208 patients -- 60% of whom were in the roflumilast group,and 40% of whom were in the placebo group. However, even though there were more cancers in the roflumilast group, many believe these cancers were not caused by the drug because most of the tumors were identified months after treatment, which would be too soon for the drug to have a causative effect. The most common side effect was nausea and diarrhea, and this was the most common reason that the 14% of patients stopped taking the drug. There seemed to be a signal for psychiatric conditions, including suicidality, but again, it is unclear that the drug actually caused this.
Every drug has risks and benefits. My guess is that aspirin would not be approved by the FDA today, since it has an increased risk of GI bleeding, other medications can relieve pain, and the benefit of heart attack and stroke prevention is controversial. The key is to balance these risks and side effects. If there are safer, more effective and similar drugs, then there is no reason to approve a new one. However, in many cases, it is better to have a drug with some known risks associated with it available to patients who have failed other therapies, then to not have the drug available at all. The FDA could have easily approved the Daxas and recommend it for patients who were still symptomatic on more standard therapy. Now, physicians will not have this medication in their tool kit for the select few patients who might actually benefit from the drug.
I believe that because the FDA has come under so much scrutiny regarding drug safety, it has made decisions where risk and benefits were not balanced appropriately. Because of the Avandia scare (which has since been proven to be unwarranted see For the RECORD, Avandia does not cause heart attacks), it is now difficult for any new diabetes drug to be approved. I also recently mentioned how unwarranted safety concerns by the FDA will likely harm far more asthma patients then help (see FDA Blows it on LABA Safety ). When safety or the need to get new drugs on the market is such a major driving force, patients are harmed, regardless of which direction the pendulum is swinging. The safety folks seem to be in the driver's seat and may be harming patients by not giving them access to needed medications. It is time for the FDA to start taking a more balanced approach to approving medications.
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