Opinions about theophylline and asthma

[mustang sally]

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Hey guys,
Assume the following scenario:

Younger African American male is using low dose fluticasone with sustained release theophylline and a rescue inhaler for his asthma (alternative therapy for step 3). Currently his asthma is not well controlled.

The NHLBI guidelines suggest that you switch to preferred therapy (low dose ICS plus LABA) before stepping up. I don't have any clinical experience, so my question is why do patients get prescribed theophylline in the first place? My ideas for this particular patient were:

1. cost/socioeconomic reasons?
2. His dr. read the SMART trial and doesn't think a LABA is safe for an African American.

 

[rxlea]

Does he have chronic bronchitis?

 

[mustang sally]

No.

 

[npage148]

The majority of Drs I see use Theo are 100 years old and don't know any better or the pt is 100 years old and has been taking theo since it was first marketed. I can only think of 1 person using it as a last resort after failure other therapy. If the Dr. is concerned about socioeconomics, he should start by calling GSK, Astra, or Schering and get the patient on a discount program

 

[spacecowgirl]

Is a combo inhaler any more expensive than Flovent?

 

[mustang sally]

The majority of Drs I see use Theo are 100 years old and don't know any better or the pt is 100 years old and has been taking theo since it was first marketed. I can only think of 1 person using it as a last resort after failure other therapy. If the Dr. is concerned about socioeconomics, he should start by calling GSK, Astra, or Schering and get the patient on a discount program

That's sort of what I figured. I just wondered if there were any legitimate reasons to be prescribed theophylline (other than treatment failure).

 

[mustang sally]

Is a combo inhaler any more expensive than Flovent?

I think combination therapy might be a bit more expensive than Flovent. But that's not taking into the account the cost of the theophylline, either.

 

[PumpkinSmasher]

That's sort of what I figured. I just wondered if there were any legitimate reasons to be prescribed theophylline (other than treatment failure).

Outside of asthma treatment there are some legit reasons to see theophylline.

 

[Old Timer]

My question is why do patients get prescribed theophylline in the first place? :

The answer is, his doctor is older than dirt. If you Google:

theophylline phosphodiesterase inhibitor

You will see some interesting articles from the 80's & 90's that postulated that theophylline was effective at lower doses (does that would produce blood levels lower than 10-20 mcg/ml) as an anti- inflammatory agent. There was even a study using it for atoptic dermatitis.

I would suggest that since there are no recent studies that theory was never proven.

Theophylline works as a phosphodiesterase inhibitor. Increasing intracellular cyclic amp and thereby leading to bronchodilation. Since the real cause of asthma is inflammation and not bronchoconstriction, there is no good reason to use this agent in asthma.

As for LABA, I would use these agents as little as possible. If you need an LABA, I would only use them with a steroid and I would would withdraw them as soon as the patient is stabilized
​

 

[Pharmavixen]

As for LABA, I would use these agents as little as possible. If you need an LABA, I would only use them with a steroid and I would would withdraw them as soon as the patient is stabilized

On what basis? Not the concomitant steroid part, but the w/d part. SABAs have been found to increase the risk of exacerbations, and some epidemiological studies have found an increased risk of death (mainly with fenoterol). OTOH, daily use of formoterol + budesonide reduces the incidence of severe exacerbations & reduces the total daily dose of inhaled steroid needed to achieve better asthma control (COMPASS trial).

And the SMART trial sucked.

 

[PumpkinSmasher]

As for LABA, I would use these agents as little as possible. If you need an LABA, I would only use them with a steroid and I would would withdraw them as soon as the patient is stabilized
​

Withdraw it so you can increase the chance patient ends up back in the emergency room? GINA guidelines disagree with you.

 

[rxlea]

OK can someone tell me why the SMART trial sucked?

EDIT: funny, the GINA guidelines include theophylline as an alternative http://www.ginasthma.com/Guidelineitem.asp??l1=2&l2=1&intId=1920

 

[All4MyDaughter]

The SMART trial showed increased risk for complications and death in African Americans on LABA. But it was a subgroup analysis. Also the trial ended early. I can't remember much else about it. I don't remember if the patients were on LABA + ICS or if the LABA was unopposed.

Even though theophylline is 3rd or 4th line treatment, I still see it used a lot because physicians like it and some patients prefer it. But, I saw a lot of weird things in the pulm clinic on my last rotation.

For the patient in the OP, I agree with adding LABA to his ICS therapy. I'm +/- on d/c'ing the theophylline.

 

[Pharmavixen]

OK can someone tell me why the SMART trial sucked?

Sure thing! The study looks impressive because they recruited > 25,000 pts. But what they actually did was bring them in for ONE SINGLE clinic visit, at which time the participants were provided with a 28-week supply of salmeterol inhalers. Pts were then followed up by telephone only q4 weeks x 28 wks. There was no way of ensuring compliance or that they weren't giving them to their family members or selling them to their neighbours, etc.

It was one of those studies where you had lots of people without medical insurance signing up to get free meds.

Considering that there was no f/u except by telephone, there's no data to help explain why African Americans suffered a higher mortality rate from the salmeterol. It's true that 49% of Caucasian pts used an ICS at baseline compared with 38% of African-Americans, but that was just at baseline. ICS use was not evaluated throughout the trial, and ICS use was an underpowered, post hoc analysis.

The investigators speculate that there are genetic differences in African-Americans to explain the higher death rate; however, African-American pts had worse asthma disease @ baseline.

I'm gobsmacked that they would go to the trouble and expense of signing up > 26,000 pts for a trial, supplying them with 7 months' worth of medication, and then only f/u by telephone. WTF?

There's an FDA meta-analysis that looked at risks from LABAs, and included data from the SMART trial. All deaths associated with LABAs were from salmeterol. Formoterol didn't seem to have the same risks.

I'm asthmatic, and I use Symbicort.

 

[Pharmavixen]

The trouble with theophylline is its narrow therapeutic index & it's a major substrate for CYP 1A2 & 3A4, so there's many potential drug interactions that can push it into toxic territory; ie, macrolides (except azithromycin) and the FQs.

 

[Old Timer]

Withdraw it so you can increase the chance patient ends up back in the emergency room? GINA guidelines disagree with you.

Well the FDA disagrees with you:

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.

F.D.A. Web Site

 

[PumpkinSmasher]

Well the FDA disagrees with you:


F.D.A. Web Site

FDA says so is such a lazy answer just like my GINA guideline response was lazy too. If you take the time to actually read the SMART trial, COMPASS, and post-SMART trial meta-analysis done by GSK and one by the FDA you may look at the FDA's position statement a little differently.

Take a look at:
-Maintaining asthma control in persistent asthma: Comparison of three strategies in a 6-month double-blind randomised study
-Randomized Comparison of Strategies for Reducing Treatment in Mild Persistent Asthma
-For the love of all that is holy, read the Methods section and inclusion criteria for SMART!!! Look how the patients were followed and assessed during the study.
-Read the meta-anaylsis
-Read fda advisory panel's statement on adviar safety

I am not saying LABA therapy should always be continued in every stabilized or discontinued in every stabilized patient. It will come down to that patient's history, analysis of the data, and treatment guidelines.

I am not going to walk into rounds and say "FDA says so". I am sure that would go over well.🙄 And making treatment recommendations is not the job of the FDA.

 

[Pharmavixen]

Regarding what the FDA said:

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.

I was going to say what Pumpkin Smasher said, regarding the SMART trial, the FDA MA, and COMPASS (I had my dr put me on Symbicort after I read the COMPASS trial). I'd add, gov't bodies like the FDA sometimes make recommendations that aren't entirely evidence-based. For instance, the FDA also says this:

LABAs do not relieve sudden-onset asthma symptoms. A rescue inhaler, such as an albuterol inhaler, should be prescribed to treat sudden asthma symptoms.

Formoterol is a LABA that does work as a rescue tx, just like a SABA, which makes sense because it's basically tweaked fenoterol. But for some reason, the FDA doesn't approve the use of formoterol as a rescue inhaler, even though it's been validated by a couple of good trials, including the COMPASS trial. In other jurisdictions, the use of formoterol is approved for use as a rescue tx, like in Canada. But not the US. It mystifies me.

 

[Old Timer]

It's real simple, I don't like drugs with black box warnings with increased incidence of death. I avoid them, if possible. It makes imminent sense to use LABA's if you cannot control the asthma with inhaled steroids. But at the same time if the patient is stabilized and can be stepped down, it's prudent. I am a minimalist and I like to use the least number of drugs and drugs with the fewest side effects. Since the main pathophysiology of asthma is airway inflammation, that's where I would like to direct my pharmacologic efforts.

 

[Pharmavixen]

It's real simple, I don't like drugs with black box warnings with increased incidence of death. I avoid them, if possible. It makes imminent sense to use LABA's if you cannot control the asthma with inhaled steroids. But at the same time if the patient is stabilized and can be stepped down, it's prudent. I am a minimalist and I like to use the least number of drugs and drugs with the fewest side effects. Since the main pathophysiology of asthma is airway inflammation, that's where I would like to direct my pharmacologic efforts.

Generally speaking, this is also my MO. Coupla points, however:

• The black box warning for LABAs is largely based on one single study, admittedly large, but poorly done;
• If asthma is inadequately txed, there may, over time, develop an irreversible component to the bronchoconstriction as airway remodelling starts occurring;
• Some asthma patients, like those who smoke or who have more severe disease, may have asthma that is neutrophil-predominant, in which case their disease is poorly responsive to corticosteroids;
• Many studies have found that patients given LABAs require lower doses of inhaled steroids than if they are maintained on steroids alone.

 

[Old Timer]

Generally speaking, this is also my MO. Coupla points, however:

• The black box warning for LABAs is largely based on one single study, admittedly large, but poorly done;
• If asthma is inadequately txed, there may, over time, develop an irreversible component to the bronchoconstriction as airway remodelling starts occurring;
• Some asthma patients, like those who smoke or who have more severe disease, may have asthma that is neutrophil-predominant, in which case their disease is poorly responsive to corticosteroids;
• Many studies have found that patients given LABAs require lower doses of inhaled steroids than if they are maintained on steroids alone.

I disagree. There were three studies the FDA used. The Smart Study, The SNS study and an FDA meta analysis.

I don't propose to inadequately treat anyone. I propose that ICS be used before LABA's and ICS/LABA combinations. I further agree with the FDA that if a patient is out of control and is brought into control with an ICS/LABA combination that the prescriber should attempt to wean the patient of the LABA to see if they can maintain their control on ICS therapy alone.

I reiterate, I don't like to treat patients long term with agents that have a black box warning referencing premature death. I think there is no good safety data on the long term use of LABA/ICS combos and therefore absent proven safety over the long term, the prudent thing to do is use these agents as little as possible for the shortest period of time.

 

[Pharmavixen]

Finally I had some time to look into this a little further...

I disagree. There were three studies the FDA used. The Smart Study, The SNS study and an FDA meta analysis.

I should have clarified: 45% of the pts in the FDA MA were participants in the SMART study, a highly problematic study as I previously mentioned (no f/u except by telephone, no verification of compliance). As for the SNS: the FDA citing the SNS study as justification for not using salmeterol long term is especially puzzling considering that pts in this trial using salmeterol had significantly better asthma control, and there was no significant difference in death rates between salbutamol and salmeterol. OTOH, many studies, both clinical trials and epidemiological studies, have found the daily use or over-use of SABAs to be associated with an increased incidence of asthma exacerbations. And some studies have found the use of SABAs associated with increased risk of death (mostly with fenoterol).

What the Canadian Thoracic Society says:

Our committee cautions that the FDA recommendation that “LABA be used for the shortest duration possible to achieve control of asthma symptoms and then discontinued” is not evidence based.

Our regulatory bodies - FDA and Health Canada - will make decisions on the basis of politics rather than what the evidence shows. If we follow what the FDA says and back off with treatment whenever asthmatics show clinical improvement, these patients subsequently then experience exacerbations. The recurrent inflammation of the airways puts these patients at risk of permanent remodelling of their airways, leading to an irreversible aspect to their bronchoconstriction.

 

[Old Timer]

Finally I had some time to look into this a little further...



I should have clarified: 45% of the pts in the FDA MA were participants in the SMART study, a highly problematic study as I previously mentioned (no f/u except by telephone, no verification of compliance). As for the SNS: the FDA citing the SNS study as justification for not using salmeterol long term is especially puzzling considering that pts in this trial using salmeterol had significantly better asthma control, and there was no significant difference in death rates between salbutamol and salmeterol. OTOH, many studies, both clinical trials and epidemiological studies, have found the daily use or over-use of SABAs to be associated with an increased incidence of asthma exacerbations. And some studies have found the use of SABAs associated with increased risk of death (mostly with fenoterol).

What the Canadian Thoracic Society says:



Our regulatory bodies - FDA and Health Canada - will make decisions on the basis of politics rather than what the evidence shows. If we follow what the FDA says and back off with treatment whenever asthmatics show clinical improvement, these patients subsequently then experience exacerbations. The recurrent inflammation of the airways puts these patients at risk of permanent remodelling of their airways, leading to an irreversible aspect to their bronchoconstriction.

I still disagree. I don't like these drugs and would only use them if the patient were not controlled on ICS. Based on what I see on a daily basis these drugs are used as first line therapy in asthma. The sheer amount of Advair v Flovent is stunning. It's not like more than a fraction have failed on ICS. It's these patients that should have never been on LABA in the first place or stepped down when asthma is controlled.

The current NHLBI guidelines agree with me:

ICSs are the most effective long-term therapy available for mild, moderate, or severe
persistent asthma; in general, ICSs are well tolerated and safe at the recommended
dosages

• LABAs are not to be used as monotherapy for long-term control of asthma
• LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children ≥5 years of age and adults)
• Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths ≥12 years of age and adults
• In the opinion of the Expert Panel, the beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the dailyuse of LABAs
• For patients ≥5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA.
• For patients ≥5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy.

• LABA may be used before exercise to prevent EIB (Evidence A), but duration of action does not exceed 5 hours with chronic regular use. Frequent and chronic use of LABA for EIB is discouraged, because this use may disguise poorly controlled persistent asthma
• In the opinion of the Expert Panel, the use of LABA for the treatment of acute symptoms or exacerbations is not currently recommended.

• National Heart Blood and Lung Institute Guidelines

I understand the concern about stepping down. Based in the science I would agree with you. But based on reality and the number of patients who are inappropriately on LABA therapy without an adequate trial of ICS, I feel the FDA recommendations are prudent. I certianly agree anyone who steps down and looses control should be on LABA therapy. This would be a small minority of the patients that are presently on LABA therapy.