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Controversies in the Pharmacotherapy of Acute Asthma: A Debate

Topic 1: Inhaled Corticosteroid Therapy in the Emergency Room- Advantage or Not?

Con: Leslie Hendeles, PharmD
Asthma is a huge problem in American Emergency Departments (ED) accounting for roughly 2 million patient visits each year. Of these, between 10% and 20% are admitted with a similar percentage relapsing within two weeks of discharge from the ED. Controversies persist over the treatment options available to the Emergency Physician.

“Although the main focus of this presentation is the role of inhaled corticosteroids (ICS) in the ED, we can’t discuss this subject without also touching on home use to prevent an ED visit,” said Leslie Hendeles, PharmD, Professor of Pharmacy and Pediatrics at the University of Florida.

A study by Wilson and Silverman enrolled 24 children, five years of age who were followed for two years. They were randomly assigned to beclomethasone in a chlorofluorocarbon (CFC) formulation by metered-dose inhaler (MDI) at a high dose of 750 micrograms a day or placebo. All children had access to beta-agonists as needed. The endpoints were prednisone use, hospitalization, symptoms, and beta-agonist use.

Use of oral corticosteroids increased in the placebo groups, although not to a statistically significant degree. Hospitalizations were not significantly altered by administering beclomethasone and there were no differences seen in adverse effects (Wilson NM, Silverman M.Arch Dis Child. 1990;65:407).
Garrett and others enrolled 28 children between 6- and 14-years-old using inhaled steroids. They were told to double their maintenance dose of
beclomethasone when an exacerbation was beginning. Symptom scores and peak flows were the main endpoints (Garrett J, et al. Arch Dis Child. 1998; 79:12).

“No significant differences were found in daily morning peak flow or symptom scores over the two-weeks of the study,” said Dr. Hendeles. “Despite a doubling of the ICS dose, symptoms and pulmonary function did not improve more than maintaining their regular dose.”

Schuh and colleagues did a large study of 100 children over 5 years-of-age with FEV1 baseline of 35% predicted. There was no placebo used for ethical reasons. All received aggressive bronchodilator therapy with a first dose of aerosolized albuterol containing ipratropium. One group was given 2000
micrograms of fluticasone via MDI and the second was given a single 2mg/kg dose of prednisone. They measured FEV1 at 4 hours and hospital admission rate. (Figure 1)

They found a significantly larger (19% vs. 9%) improvement in 4-hour FEV1 among those in the oral corticosteroids group when compared with children given fluticasone. There was also a drastic reduction in hospitalizations (10% vs. 31%) in the oral corticosteroids patients (Schuh S, et al. NEJM. 2000; 343:689).

“This study very clearly demonstrated that oral, systemic administration of corticosteroids was significantly more effective than monotherapy with inhaled corticosteroids,” noted Dr. Hendeles.

Dr. Rubin’s group studied the impact of different treatments following release from the ED. They focused on 58 children aged 6 to 16 years with FEV1 upon discharge from the ER at 45% of predicted. One group was given prednisone 2 mg/kg every day for five days while the other got flunisolide 1000
micrograms twice a day, twice the normal maintenance dose (Nakanishi AK, et al. Chest. 2003;124:790).

They found FEV1 was significantly greater at three days in the group getting the oral corticosteroids when compared with those prescribed inhaled steroids. There was no difference in the symptoms.

Dr. Hendeles suggests these concerns for physicians. One is adequate early penetration when using inhaled medications, especially in the more severely obstructed patient. The second issue is lack of efficacy, at high or even doubled doses.

A third consideration is whether it is fair to compare twice-a-day inhaled steroids to a once-a-day oral cortico-steroids regimen. He noted that there is data to suggest that the effects of a single dose of corticosteroids wears off in about 12 hours.

“Finally, inhaled steroids are much more expensive and less convenient to use in treating acute symptoms,” he noted. “Based on the available evidence, it appears that ICS should not be used routinely as a substitute for oral corticosteroids in the treatment of acute exacerbations in asthma.”

Pro: Richard Nowak, MD
Bronchodilators and corticosteroids are the first line of asthma therapy in the ED, according to Richard Nowak, MD, Vice-Chair, Department of Emergency Med-icine at Henry Ford Hospital in Detroit. The therapeutic question is which route, timing and amount best addresses the concerns of ED physicians.

“If you review the literature, it becomes clear that the optimal agent, dose, frequency and delivery of therapy remains unsettled,” he said. “Asthma is not a systemic inflammation, it is inflammation in only one organ — the lung. The question then becomes does it make sense to deliver inflammatory medicine only to the appropriate organ?”

Dr. Nowak based his presentation largely on a recent Cochrane Library review by Edmonds and others. This review was built on seven different randomized-controlled or quasi-controlled trials. A total 376 of patients were enrolled. Of these, 191 were given ICS and 185 were not. The steroids used included beclomethasone, budesonide and flunisolide. Spacers and nebulizers were used to deliver the medication (Edmonds ML, et al. Cochrane Data Base System Review. 2001. CD:0002308).

Overall, patients treated with ICS were less likely to be admitted to the hospital. When inhaled and systemic steroids were combined, the addition of the ICS benefited the patient. Those taking ICS also demonstrated a small but significant improvement in peak expiratory flow. Importantly to Dr. Nowak’s view, the inhaled medications were well tolerated with fewer adverse side effects. Specifically, the researchers stated there was no evidence of increased bronchoconstriction with the use of ICSs.

“In the secondary analysis comparing ICS with systemic steroids, it turns out that there is a lot of heterogenicity between the studies,” stressed Dr. Nowak. “This means they couldn’t come up with any definite recommendations.”

Rodrigo and colleagues looked at severe asthmatics with pulmonary function tests (PFT) less than 50% of predicted. They were randomized to a medication regimen via MDI every 10 minutes for three hours. The patients were divided into three groups and given either albuterol/ ipratropium/flunisolide, albuterol/flunisolide or albuterol/ipratropium (Rodrigo G, Rodrigo C. Am J Respir Crit Care Med. 1998; 157:698). (Figure 2)

In those with milder disease, there appeared to be no differences in hospital admissions. In the sicker patients, <30% predicted, the 32% admitted using the albuterol/ipratropium compared favorably with 28% hospitalized using albuterol/flunisolide and only 10% in the group where all three were used.

“This review indicated that ICS reduces hospital admissions when used early in exacerbations with no associated significant side effects,” said Dr. Nowak. “Therefore, while I think it is appropriate to use ICS in acute asthma, we don’t yet know the right dose or the optimal agent and studies on this
aspect should continue. I also think it is reasonable to begin to consider no longer using systemic corticosteroids, especially in mild to moderate acute
asthma.”

Nebulized Beta-Agonists in the ER: Levalbuterol or Racemic Albuterol?

Con: Dr. Hendeles
To explore the relative potency of two of these medications, Dr. Hendeles and colleagues randomized patients with nocturnal asthma attacks (NA) to two treatments in a cross-over manner. One was 2, 4, and 8 puffs of albuterol delivered via MDI; the other was the same dosage of Primatene Mist.

By plotting the percentage of maximal possible improvement in FEV1 for each of the medications, they found the dosages needed for comparable results. For example, an improvement of 50% requires two puffs of albuterol. It is then possible to extrapolate that it would take about 4 puffs of epinephrine to get the same improvement in symptoms (Marshik P, et al. Am J Resp Crit Care Med. 1997;155:A672).

“What that says is because there was a statistically significant dose-response relationship, the slope of the line was greater than 0,” said Dr. Hendeles. “Because the two treatments were parallel and overlapping, you could estimate the relative potency between the two.”

This he contrasted with the results of a study by Milgrom and colleagues of children with stable asthma comparing levalbuterol and racemic albuterol. The dose of the levalbuterol ((R) isomer only) was 0.31 mg and 0.63 mg and for racemic (both the (S) and (R) isomers) the doses were 1.25 mg and 2.50 mg. Peak FEV1 response was flat in both instances (Milgrom H, et al. J Allergy Clin Immunol. 2001;108:938). (Figure 1)

“This means that you really can’t make any kind of estimate,” said Dr. Hendeles. “If you can’t distinguish between two doses of either the test or reference product, then you can’t compare one to the other.”

“The spin on the published article was that .31 mg of levalbuterol was just as effective as 2.5 mg of racemic,” he continued. “The response in these children is at the top of the dose-response curve and so all of the doses may be in excess of what is needed to maximally bronchodilate these stable patients. If they had given a lower dose of racemic, it may have been just as effective.”

A paper by Nelson and others is also often quoted as proof of greater benefit to using levalbuterol. They studied two doses of both levalbuterol and racemic as well as a placebo. They noted a difference in peak effect after the first dose of 1.25 mg of levalbuterol that was slightly but statistically higher than 2.5 mg of racemic. By the final dose at 28 days there were no differences noted (Nelson HS, et al. JACI.1998:102:943).

“It is suggested that the (S) isomer of albuterol accumulates in the airways because of a longer half-life and antagonizes the effects of the (R) isomer,” said Dr. Hendeles. “If this were the case, why would the first dose’s effect be substantially higher than the last? I would expect the opposite with (S) build up.”

Another study by Lotvall and others examined the response to RS albuterol, (R) or (S) albuterol alone or placebo. They found improvement in lung function was the same at each timepoint when using equimolar doses so that RS delivers the same amount of (R). In this case, lung function seen with (S) alone was not significantly different from placebo. They found that delivering the same amount of R-albuterol results in the same effect whether it comes from racemic or levalbuterol (Lotvall J, et al. J Allergy Clin Immunol. 2001;108:726).

“What this shows is that levalbuterol is neither more effective nor safer than racemic,” said Dr. Hendeles. “It is, however, much more expensive.”

Pro: Dr. Nowak
“Racemic albuterol is two drugs- the (S) and the (R) isomers,” said Dr. Nowak. “When this drug was initially released 35 years ago, you did not need to study the different isomers since you couldn’t separate them. Essentially you have two drugs that are being given, one has been studied and one has not.”

Now that it is possible to distinguish between the two, it is also possible to analyze the (R) and (S) isomers in the preclinical area. There is good evidence that the (R) isomer is clinically active and it was long thought that the (S) isomer was inert. There is, according to Dr. Nowak, quite a bit of data suggesting the (S) isomer is not as inert as once thought.

“As a matter of fact, the data indicates that the (S) isomer of albuterol is spasmogenic, proinflammatory, decreases mucocilliary clearance and
actually mimics the disease you are trying to treat,” he said. “This may explain why some people getting large amounts of albuterol to manage their disease actually do worse. It may be the selective accumulation of the (S) isomer of albuterol.”

The problems may arise because the (S) isomer may be broken down ten times more slowly than the (R) isomer. When a patient is given back-to-back racemic treatments, they may selectively accumulate the (S) isomer.

“Two studies by Milgrom and Nelson, discussed by Dr. Hendeles, have nothing to do with acute disease and I would disregard for purposes of this discussion,” said Dr. Nowak. “These do not reflect the way we treat acute disease and is not the way the medication is to be used according to FDA recommendations.” (Figure 2)

Dr. Nowak studied a group of patients with FEV1 measurements of 20% to 55% of predicted who were given either racemic albuterol or levalbuterol. Participants were administered the medications three times for the first hour according to guidelines, there was an hour wait and then reassessments using repetitive PFTs to follow changes.

They noted that a very low dose of levalbuterol (.63 mg) got basically the same bronchodilator effect as racemic 5.0 mg but there is a lot more (R) isomer involved with the racemic dose suggesting that the S isomer is, in Dr. Nowak’s words, “misbehaving”. The levalbuterol 1.25 mg was statistically the better bronchodilator in this group.

“After each dose in acute disease, there was the same amount of (R) in each,” said Dr. Nowak. “One happens to be with (S) and one not. I would
argue that indeed the (S) isomer is not inert and what you see is its adverse effects. It is actually competing with what you are trying to accomplish using the (R) isomer.”

There is no question that (S) isomer is accumulated. Patients getting 15 mg of racemic albuterol in the first hour of treatment had (S) levels above 8,000 picograms/ ml when measured at two hours.

The question then becomes whether these levels have a clinical impact and Dr. Nowak suggests they do. They looked at 630 patients with FEV1
between 20% and 55% of predicted then compared 1.25 mg of levalbuterol with 2.5 mg of racemic albuterol in a head-to-head study. The results have been submitted for presentation in greater detail at a meeting in early 2004 (Society of Academic Emergency Medicine and American Thoracic Society).

“When you look at the data, the pattern of the single isomer being a better bronchodilator on a milligram-to-milligram basis persists,” he said. “This was also reflected by lower hospital admission rates in the patients receiving levalbuterol. The pattern of (S) isomer accumulation in those given racemic
albuterol associated with less improvement in PFTs also persisted.”

A study of emergency room presentations backed up these conclusions. Schreck enrolled 922 consecutive cases presenting to emergency rooms over a 12-month period. They compared levalbuterol to albuterol with the endpoint of admission rates. There were no significant differences in study-admission status between the two groups and they treated both children and adults (Schreck D. National Association of EMS Physicians meeting, 2003; Panama City, FL).

Upon analysis of the data, they found significantly less hospital admissions among those taking the single isomer medication. The admission rate for RS albuterol was 17.4%, which is consistent with the general rate of admission in the United States (10% to 20%). This number was reduced to 7.8% with
single isomer medication.

A study by Carl from Children’s Hospital in Cleveland, OH, compared 2.5 mg of racemic to 1.25 mg of (R) in a blinded fashion and used an objective scoring system for making treatment decisions. Again, there was a drop in admission in the group getting the single isomer medication. Since the participants received the same amount of (R) isomer, Dr. Nowak suggests the difference is related to clinically relevant adverse effects of the (S) isomer (Carl JL, et al. J Pediatrics. 2003;143:731).

Dr. Truitt and others completed a retrospective study looking at ways to reduce the amount of therapy given to hospitalized patients. They studied six months of racemic and six months of levalbuterol therapy. During the racemic period, participants received 2.5 mg or placebo every 4 hours. They then were prescribed 1.25 mg of levalbuterol to maintain the same levels of (R). Rescue medications were given as needed to both groups (Truitt , et al. Am J Resp. Crit Care Med. 2001;161:A553).

Of those getting racemic albuterol, almost one in five required more racemic therapy compared to 6% in the single isomer cohort. The (R)-only patients needed less rescue medications despite getting the same amount of (R) isomer, again suggesting that there was a problem with the (S) isomer. In addition, those on levalbuterol had a trend (p=0.58) of earlier discharge.

“Based on the sheer weight of the acute data, I think intelligent people can only conclude that levalbuterol is superior bronchodilator when compared to racemic,” said Dr. Nowak. “I also think that non-inertness of the (S) isomer has important and problematic clinical manifestations.”


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