THE NEWS

‘Common Asthma Inhalers can be Fatal'

These type of irresponsible articles have featured in newspapers and on the net which have raised concern amongst patients and doctors regarding asthma treatment. The following facts with a detailed update on the controversy is an attempt to clarify the issue. This would help the clinicians to get the real picture and help them in clearing their patient’s queries.

The FACTS

• These reports have been based on a recent study (meta-analysis) published in the journal Annals of Internal Medicine, comparing patients receiving LABA vs placebo, showing an increase in asthma related events in the LABA group.
• Nearly half of the patients in the study were not receiving inhaled corticosteroids . LABAs given as monotherapy might cause deterioration of asthma since they do not control the underlying inflammation.
• There is no comparison of ICS/LABA combination (salmeterol/fluticasone & formoterol/budesonide) with placebo in this study, hence the results cannot be extrapolated to the ICS/LABA combination
• ICS/LABA combinations have been used in the form of separate inhalers or as single inhalers for over a decade now
• The introduction of the combination inhalers have revolutionized asthma treatment worldwide. These combinations have benefited millions of asthmatics across the globe.
• Internationally the combination Salmeterol/Fluticasone has become the 3 rd largest selling drug
• Since the launch of these combinations in India , doctors have gained trust and faith in them . These combinations have been used for almost 6 years now without any reports of any significant serious events.
• The data obtained from the study merely reiterates the fact that treatment of asthma primarily remains inhaled corticosteroids. LABAs are add on agents to be used if patient is not controlled on low to medium doses of inhaled steroids.
• Since the launch of salmeterol in the 1990s the number of asthma deaths have actually decreased

It should be noted that

• LABAs should never be used alone.
• Combination inhalers (ICS/LABA) are safe in patients inadequately controlled on low to medium doses of ICS. The ICS component controls the inflammation and addition of LABA provides symptom relief and ensures the continuation of ICS therapy.

Detailed Update on the LABA Controversy

Asthma is a chronic inflammatory disease and the first line treatment of asthma is inhaled corticosteroids. The inhaled long acting beta-agonists (LABAs) salmeterol, formoterol were introduced in the 1990s. This class of drugs produce bronchodilation and improve asthma symptoms and lung function. However, they have been shown to have no clinically significant effect on airway inflammation. Hence, monotherapy with LABAs has consistently been shown to be inferior to the use of inhaled corticosteroids, and is not recommended

The recent controversy on the use of LABAs is based on a study published in Annals of Internal Medicine June 2006. This is a meta-analysis (compilation of many different studies) including all those studies comparing LABAs with placebo, for duration of at least 3 months. In all 19 studies were selected, involving 33,826 patients. Patients receiving LABAs were found to be 2.5 times more likely to be hospitalized and about 2 times more likely to have life-threatening asthma attacks than those receiving placebo.

However it should be noted

• 47% of the patients were not receiving inhaled corticosteroids
• 78% of all asthmatic patients in this meta-analysis were from Salmeterol Multicenter Asthma Research Trial (SMART) study. The results of the SMART study indicated a higher number of asthma-related life-threatening experiences among the African-American patients as compared to Caucasian patients. This was because -
  • There was minimal use of inhaled corticosteroids across all the patients recruited in the SMART study
  • African-American patients had more severe asthma, indicated by lower peak flow rates, less ICS use, higher incidence of intubations, emergency room visits and hospitalizations as compared to the Caucasian patients, which could be the reason for the high casualties .
  • In the SMART study patients receiving corticosteroids along with LABA showed similar asthma related deaths and life-threatening experiences compared to the placebo groups. Guidelines say that LABAs should be used only with corticosteroids because although they open the airways and make the patient feel better, they don't reduce the underlying inflammation, which triggers asthma attacks. Poor outcomes in the SMART study might be because they weren't treating the underlying inflammation.

Implications of the Meta-Analysis

•  LABAs should not be used as first line treatment for asthma

•  LABAs should be added only if other medicines, including low-to medium-dose corticosteroids, do not control asthma

•  LABAs are not a replacement for inhaled corticosteroids, which should be continued at the same dose, and not stopped or reduced, when treatment with LABA is initiated. Thus LABAs should never be used alone in the treatment of asthma.

•  Patients should be educated to recognize the signs of deteriorating asthma like increased use of short-acting bronchodilator and the need to seek medical attention promptly in such circumstances.

In fact 2 earlier landmark studies, viz. FACET and GOAL had shown that ICS/LABA combination was superior in controlling asthma.

The Formoterol And Corticosteroid Establishing Therapy (FACET) has reported that in patients with persistent symptoms of asthma despite treatment with low to moderate doses of corticosteroids, addition of formoterol to budesonide therapy is beneficial in terms of improving symptoms and lung function and reducing total number of exacerbations , without lessening the control of asthma. Similar results were reported in the recently published Gaining Optimal Asthma Control (GOAL) study involving 3,421 patients with uncontrolled asthma. Salmeterol/fluticasone combination helped to achieve sustained control of asthma in more patients, more rapidly and at a lower dose of inhaled corticosteroids than fluticasone alone

All international guidelines on asthma management recommend the use of anti-inflammatory therapy for the treatment of asthma, with inhaled corticosteroids (ICS) being the first choice of treatment. The current study merely reiterates earlier findings. Inhaled corticosteroids are anti-inflammatory in nature, thus reducing the hyperresponsiveness and frequency and severity of asthma attacks. Long acting b2 -agonists like salmeterol are not to be used alone, since they do not act on inflammation, but merely relieve bronchospasm. They have to be always used along with ICS. Hence combination inhalers containing ICS and LABAs are absolutely safe and effective for asthma patients

Inhaler -associated deaths in asthma & the truth
Dr S.K. Jindal

T HERE is a general alarm caused by a recent report on asthma deaths which appeared in the prestigious medical journal Thorax and was widely quoted in the lay Press by different news agencies. I have personally received queries from patients and other people from different walks of life on the implications and details of the results of the investigations reported by Stephan Lanes who attributed up to 50-fold increased risk of death associated with an excessive use of inhalers to seek relief from asthma.

There are several finer points and qualifications in the conclusions which tend to escape the attention of general readers thereby leading to erroneous impressions and conclusions. The fact of the matter is that inhalational therapy continues to remain the most effective and the safest form of treatment of asthma and there is no real cause of fear.

The fear of death from an excessive use of inhalers is not new. It was in the 1960s when a temporal relation was discovered in the UK between the increase in asthma deaths and increased over-the-counter sales of isoprenaline a nonspecific beta agonist inhaler. Based on the circumstantial evidence linking this “epidemic” of asthma deaths with inhalers, the over-the-counter sale of isoprenaline was stopped. The second epidemic was reported from New Zealand in the late 1970s targeting fenoterol — another beta agonist. The causal association could never be proved but the drug did go into disrepute.

What are the inhalers and the drugs used through them? An inhaler, in fact is not a drug as such but only a device used to administer a drug in the respiratory system. Inhalers of several drugs are already available in the market and many more are waiting in the pipeline. Factually, therefore, an inhaler in itself is neither a problem nor a panacea. Inhaler is a system of administration of a drug similar to the example of a syringe to inject a drug. An inhaler is used to either convert a liquid-drug into an aerosol and release the same as a puff (metered dose inhaler) or to supply and deliver the drug in a fine powder form (dry powder inhalers — rotahalers, turbohalers, accuhalers, etc).

There are two main groups of drugs for asthma used with inhalers — relievers and preventers. The “relievers” act immediately and provide relief from acute symptoms of asthma. Bronchodilators, primarily the short and long acting beta-agonist drugs (salbutamol, terbutaline, salmeterol, formoterol and others), are the important ‘relievers”.

The “preventers” are primarily the anti-inflammatory drugs represented by locally acting corticosteroids such as the beclomethasone, budesonide and fluticasone. It is the difference between the relievers and the preventers which makes all the difference in the control of asthma and in causing any side-effects, including deaths from asthma.

It may seem a bit odd but true that the corner-stone of asthma treatment in the use of “preventers” and not the “relievers”. Although there is a rapid relief after a puff or two of a beta agonist inhalation, it does not last long and the problem comes back. One tends to take more inhalations, and more and more.... till exhaustion and frustration take over.

It is the repeated use of bronchodilator inhalations which must be avoided. As per the recent report, patients who had 13 or more relief-inhaler prescriptions in the previous year had a 50 fold risk of asthma deaths. Among 96,000 asthmatics who had their treatment data entered into the General Practice Research database in the UK , there were 43 asthma deaths.

There are multiple explanations for an excessive mortality in this group. The most important reason is the inability to control the underlying inflammation which is inadvertently allowed to continue. There is an apparent failure to recognise the early signs of deterioration because of an over-reliance on “ reliever” drugs providing a deceptive relief from symptoms. It is akin to treatment of an infection with continued use of antipyretic drugs without taking care of the underlying infection. The drug is factually innocent but gets the blame by default.

It is also likely that those patients who excessively use the beta agonists are suffering from a more severe and different-to-control asthma.

This group of patients are known to have a higher mortality. Beta agonists can also produce problems, especially the cardiac arrhythmias and death when the toxic levels are reached. All efforts must, therefore, be directed to avoid the excessive use.