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 copd. Show all posts
Showing posts with label copd. Show all posts
Monday, September 20, 2010
Wednesday, April 14, 2010
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.
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.
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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