Guias Clinicas de Asma

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Asthma, placebo, and how not to kill your patients

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Source: Science Based Medicine

A number of years ago I was walking along Lake Michigan with a friend (a fellow medical resident) when she turned to me and said, “are you wheezing?  Do you have asthma?”  I had always been physically active and assumed my breathlessness while walking down the trail was due to the thirty extra pounds of pizza and doughnuts I’d acquired during residency.  But she was right: I was wheezing and breathless and it didn’t feel good at all.  I made an appointment with one of the hospital’s lung docs who took a good history, did a physical, and ran some pulmonary function tests.  And I did have asthma.  And it felt much, much better when I            t got better when I lost 40 lbs and started treatment for my acid reflux.)

I still get mild asthma symptoms from time to time, especially when I get sick, but for many others, the picture isn’t so pretty.  Asthma kills at least a quarter of a million people every year around the world.   If you’ve ever worked in an ER and seen a kid with a bad asthma attack, you’ve earned a healthy respect for the disease.  If you’ve ever watched your own kid gasping for breath, begging you to make it better, you’ve learned to fear it.

As our understanding of asthma has improved, so has our ability to treat it (an ability that is strongly linked to a patient’s socio-economic status.  Mortality has been rising despite the discovery of better treatments.  Wait: let’s pull this out of the parentheses…)…  Asthma deaths and hospitalizations are largely preventable, and disproportionately affect Black and Hispanic Americans. We know how to treat thedisease asthma, but don’t know how to treat the people who are affected most.

We understand that asthma is not just a tightening of the airways but also an inflammation that can cause long-term damage.   Not only can we treat asthma, but we have objective ways of measuring how well our patients are doing.   It’s easy and inexpensive to measure airway obstruction and response to medications.  We know what works.
For this reason, a new study in the New England Journal of Medicineseems both wise and foolish. To see full article in PDF here. 

(I thought I was so on the ball.  I really did. But while I was busy riding my bike, playing with my kid, and looking at rentals with my wife, David Gorski and my other medical blogger pals were out in Las Vegas at TAMdiscussing the very study I wanted to tell you about.)

The study, called “Active albuterol or placebo, sham acupuncture, or no intervention in asthma,” was done for reasons that are not clear to me. It may have been done not to test the effectiveness of asthma therapy but to look at what a “placebo” might really be or do.  At least, I think that was the idea.  When reading the abstract and full text, it’s not actually clear why the study was done.  At first it seems as if it were done to see why asthmatics treated with placebo improve:

In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention.

Why ask such a question? We know that poorly-treated asthma is deadly, and well treated asthma much less so.  Why do we care about placebo effects here?  The authors explain further:

Placebo effects (i.e., benefits resulting from simulated treatment or the experience of receiving care) are reported to improve signs and symptoms of many diseases in clinical trials and in clinical practice. On this basis, the accepted standards for clinical-trial design specify that the effects of active treatment should ideally be compared with the effects of placebo. Despite this common practice, it is unclear whether placebo effects observed in clinical trials (or those that presumably occur in clinical care) influence both objective and subjective outcomes and whether placebo effects differ from the natural course of disease or regression to the mean.

In other words, the authors want to know what placebos actually do to real people, and they chose asthmatics because they are easy to study (there are symptom-assessment tools for subjective data and spirometry for objective data).   This makes asthma both the right and wrong choice for the study.  It’s an excellent model to assess the affect of placebo, but one in which the use of placebo is hard to justify on an ethical basis.

Not surprisingly, they found that “doing something” worked better than doing nothing.  More specifically, they found that any placebo will make a patient feel subjectively better than doing nothing at all.   They also found that all three placebos (sham acupuncture, fake inhaled medicine, and simply being enrolled in the study without treatment) improvedobjective measures of lung function, but not nearly as much as real medicine (in fact, not much at all).

In other words, simply attending to a patient makes them feel better.  But to get a significant objective improvement (in asthma at least) you must also give them real medicine.  Real medicine comprises both active medications and attending to the patient.  There is no separate “placebo” that can be given to treat asthma effectively.

This is actually a quite beautiful study.  It demonstrates that “placebo effect” is not the same as a real treatment, that real treatment always includes whatever benefit placebo provides, and that placebo is mostly an effect on subjective rather than objective measures of health.  You can’t fix asthma with placebo, only with real treatment.  But we’ve already known that from decades of studying asthma.  So what other justification is there for doing this study?

Our research has important implications both for the treatment of asthma and for clinical-trial design in general. Many patients with asthma have symptoms that remain uncontrolled, and the discrepancy between objective pulmonary function and patients’ self-reports noted in this study suggests that subjective improvement in asthma should be interpreted with caution and that objective outcomes should be more heavily relied on for optimal asthma care. Indeed, although improvement in objective measures of lung function would be expected to correlate with subjective measures, our study suggests that in clinical trials, reliance solely on subjective outcomes may be inherently unreliable, since they may be significantly influenced by placebo effects. However, even though objective physiological measures (e.g., FEV₁) are important, other outcomes such as emergency room visits and quality-of-life metrics may be more clinically relevant to patients and physicians. Although placebos remain an essential component of clinical trials to validate objective findings, assessment of the course of the disease without treatment, if medically appropriate, is essential in the evaluation of patient-reported outcomes. (Emphasis mine, PalMD)

Source: Science based-medicine

This is folly.  First, we have a huge literature on quality of life metrics in asthma.  Huge.  And we also know that objective changes in asthma are what save patients’ lives.  Yes, I care how my patient feels, but it is not more “clinically relevant” than how they are actually doing physiologically.  Both are important, but not equal.  And the idea that comparing active treatment to placebo is not ideal is not new to researchers.  It’s simply that following the natural history of the disease as a “control” is not usually appropriate (cf. Tuskegee syphilis experiment).

No good clinician would consider treating an asthmatic with placebo.  Improper treatment of asthma leads to debility and death.  This study chose mild asthmatics, but I still feel very uncomfortable with the ethics of the study design.  Rather than using a disease we know how to treat to study placebo, we should be finding ways to get treatment to the millions of people who aren’t getting it.

References

Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, & Kaptchuk TJ (2011). Active albuterol or placebo, sham acupuncture, or no intervention in asthma. The New England journal of medicine, 365(2), 119-26 PMID: 21751905

Related articles

• Last Week at Science-Based Medicine (randi.org)
• ‘Hearing’ Asthma – What’s a Wheeze? (everydayhealth.com)
• Could my wheezing indicate asthma? (zocdoc.com)
• Lung Function Tests for Asthma (everydayhealth.com)
• The Asthma Diagnosis Process (everydayhealth.com)
• Does asthma cause fatigue? (zocdoc.com)
• Why do I need a pulmonary functioning test after starting my medication? (zocdoc.com)
• Does spirometry help detect asthma? (zocdoc.com)
• Asthma sufferers to have Botox injected into voice box (thehandiestone.typepad.com)
• My chronic cough turned out to be adult asthma (cnn.com)
• Do You Suffer From Asthma? (fitsugar.com)
• The Placebo Effect, This Time in Asthma (blogs.wsj.com)
• Asthma Placebo Study Demonstrates Power of Expectations (abcnews.go.com)
• Researchers Use Placebo Effect To Study Asthma (inquisitr.com)
• Asthma Study Shows Placebo Can Help Symptoms (webmd.com)
• Albuterol for Asthma Control (everydayhealth.com)
• The Placebo Effect Revisited (anadder.com)
• Following an Asthma Action Plan (everydayhealth.com)
• Dangerous placebo medicine for asthma [Respectful Insolence] (scienceblogs.com)
• A closer look at the placebo effect (eurekalert.org)

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Revisa la FDA retiro de fármacos contra el asma por sus efectos

■ Pide retirar tratamientos con agonistas LABA en menores de 18 años y de Serevent y Foradil en pacientes de todas las edades

■ La semana próxima consultarán a un panel de expertos

Reuters

Washington, 5 de diciembre. Los reguladores sanitarios de Estados Unidos siguen preocupados por los graves riesgos causados por una clase de fármacos contra el asma, por lo que decidieron pedir asesoría a un grupo de especialistas externos, indicaron documentos publicados el viernes.
Los funcionarios del área de salud consultarán la semana próxima a un panel de asesores sobre si deberían revocar su aprobación para el tratamiento de la enfermedad, agregaron.
El personal de la oficina de seguridad de medicamentos de la Administración de Alimentos y Fármacos de Estados Unidos (FDA, por su siglas en inglés) recomendó de forma unánime retirar la autorización de tratamiento a menores de 18 años a todos los agonistas beta de larga duración (LABA, por sus siglas en inglés).
Las medidas se dan en medio de un aumento del riesgo de muertes y ataques relacionados con asma entre los consumidores de esos fármacos.
Entre los LABA se encuentran Advair y Serevent de GlaxoSmithKline Plc, Symbicort de Astra Zeneca Plc y Foradil de Novartis AG, que en Estados Unidos comercializa Schering-Plough Corp.
Riesgos contra beneficios
El personal de seguridad de medicamentos de la FDA, que controla los riesgos de los fármacos después de su aprobación, también instó a la remoción de la autorización de Serevent y Foradil para el tratamiento del asma en las personas de todas las edades.
Serevent y Foradil sólo contienen LABA, mientras Advair y Symbicort combinan LABA con esteroides inhalables.
Sumar el esteroide protegería contra las complicaciones graves, argumentó Glaxo.
Un “meta análisis” de varios estudios reveló que el riesgo “no se veía” en el caso de Advair o cuando el LABA se usaba con un esteroide, señalaron los documentos de la agencia federal estadunidense.
Un memorándum que resume los temas a tratar en el encuentro del panel asesor señaló que la FDA preguntará a los especialistas externos si las medicinas aún deberían tener aprobación para el tratamiento de asma. El panel se reunirá el miércoles y jueves próximos.
El doctor Badrul Chowdhury, director de la división de la FDA que revisa los fármacos pulmonares y antialérgicos, dijo que existe un “riesgo de seguridad grave e importante”, pero añadió que las muertes vinculadas con el asma eran “numéricamente escasas” y los beneficios no eran triviales.
“La remoción del mercado de los LABA inhalables como tratamiento para el asma es una forma de controlar el riesgo que implican estos medicamentos, pero se trataría de un enfoque extremo que podría resultar problemático”, escribió Chowdhury.
Los fármacos también están aprobados para el tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC) y se mantendrían disponibles para los pacientes con esa dolencia.
Los fabricantes de las medicinas, en documentos separados preparados para el encuentro, indicaron que los beneficios superan a los riesgos cuando se utilizan como es indicado.

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Revisa la FDA retiro de fármacos contra el asma por sus efectos

■ Pide retirar tratamientos con agonistas LABA en menores de 18 años y de Serevent y Foradil en pacientes de todas las edades

■ La semana próxima consultarán a un panel de expertos

Reuters

Washington, 5 de diciembre. Los reguladores sanitarios de Estados Unidos siguen preocupados por los graves riesgos causados por una clase de fármacos contra el asma, por lo que decidieron pedir asesoría a un grupo de especialistas externos, indicaron documentos publicados el viernes.
Los funcionarios del área de salud consultarán la semana próxima a un panel de asesores sobre si deberían revocar su aprobación para el tratamiento de la enfermedad, agregaron.
El personal de la oficina de seguridad de medicamentos de la Administración de Alimentos y Fármacos de Estados Unidos (FDA, por su siglas en inglés) recomendó de forma unánime retirar la autorización de tratamiento a menores de 18 años a todos los agonistas beta de larga duración (LABA, por sus siglas en inglés).
Las medidas se dan en medio de un aumento del riesgo de muertes y ataques relacionados con asma entre los consumidores de esos fármacos.
Entre los LABA se encuentran Advair y Serevent de GlaxoSmithKline Plc, Symbicort de Astra Zeneca Plc y Foradil de Novartis AG, que en Estados Unidos comercializa Schering-Plough Corp.
Riesgos contra beneficios
El personal de seguridad de medicamentos de la FDA, que controla los riesgos de los fármacos después de su aprobación, también instó a la remoción de la autorización de Serevent y Foradil para el tratamiento del asma en las personas de todas las edades.
Serevent y Foradil sólo contienen LABA, mientras Advair y Symbicort combinan LABA con esteroides inhalables.
Sumar el esteroide protegería contra las complicaciones graves, argumentó Glaxo.
Un “meta análisis” de varios estudios reveló que el riesgo “no se veía” en el caso de Advair o cuando el LABA se usaba con un esteroide, señalaron los documentos de la agencia federal estadunidense.
Un memorándum que resume los temas a tratar en el encuentro del panel asesor señaló que la FDA preguntará a los especialistas externos si las medicinas aún deberían tener aprobación para el tratamiento de asma. El panel se reunirá el miércoles y jueves próximos.
El doctor Badrul Chowdhury, director de la división de la FDA que revisa los fármacos pulmonares y antialérgicos, dijo que existe un “riesgo de seguridad grave e importante”, pero añadió que las muertes vinculadas con el asma eran “numéricamente escasas” y los beneficios no eran triviales.
“La remoción del mercado de los LABA inhalables como tratamiento para el asma es una forma de controlar el riesgo que implican estos medicamentos, pero se trataría de un enfoque extremo que podría resultar problemático”, escribió Chowdhury.
Los fármacos también están aprobados para el tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC) y se mantendrían disponibles para los pacientes con esa dolencia.
Los fabricantes de las medicinas, en documentos separados preparados para el encuentro, indicaron que los beneficios superan a los riesgos cuando se utilizan como es indicado.

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Antiasmaticos en el NYT

Warning Given on Use of 4 Popular Asthma Drugs, but Debate Remains

By GARDINER HARRIS

Published: December 5, 2008

WASHINGTON — Two federal drug officials have concluded that asthma sufferers risk death if they continue to use four hugely popular asthma drugs — Advair, Symbicort, Serevent and Foradil. But the officials’ views are not universally shared within the government.

The two officials, who work in the safety division of the Food and Drug Administration, wrote in an assessment on the agency’s Web site on Friday that asthma sufferers of all ages should no longer take the medicines. A third drug-safety official concluded that Advair and Symbicort could be used by adults but that all four drugs should no longer be used by people age 17 and under.

Dr. Badrul A. Chowdhury, director of the division of pulmonary and allergy products at the agency, cautioned in his own assessment that the risk of death associated with the drugs was small and that banning their use “would be an extreme approach” that could lead asthmatics to rely on other risky medications.

Once unheard of, public disagreements among agency experts have occurred on occasion in recent years. The agency is convening a committee of experts on Wednesday and Thursday to sort out the disagreement, which has divided not only the F.D.A. but also clinicians and experts for more than a decade.

Sudden deaths among asthmatics still clutching their inhalers have fed the debate. But trying to determine whether the deaths were caused by patients’ breathing problems or the inhalers has proved difficult.

The stakes for drug makers are high. Advair sales last year were $6.9 billion and may approach $8 billion this year, making the medication GlaxoSmithKline’s biggest seller and one of the biggest-selling drugs in the world. Glaxo also sells Serevent, which had $538 million in sales last year. Symbicort is made by AstraZeneca and Foradil by Novartis.

Whatever the committee’s decision, the drugs will almost certainly remain on the market because even the agency’s drug-safety officials concluded that they were useful in patients suffering from chronic obstructive pulmonary disease, nearly all of whom are elderly.

Dr. Katharine Knobil, global clinical vice president for Glaxo, dismissed the conclusions of the agency’s drug-safety division as “not supported by their own data.” Dr. Knobil said that Advair was safe and that Serevent was safe when used with a steroid.

Michele Meeker, a spokeswoman for AstraZeneca, said that the F.D.A.’s safety division improperly excluded most studies of Symbicort in its analysis, and that a review of all of the information shows that the drug does not increase the risks of death or hospitalization.

Dr. Daniel Frattarelli, a Detroit pediatrician and member of the American Academy of Pediatrics’s committee on drugs, said that he was treating children with Advair and that his committee had recently discussed the safety of the medicines.

“Most of us felt these were pretty good drugs,” Dr. Frattarelli said. “I’m really looking forward to hearing what the F.D.A. committee decides.”

About 9 percent of Advair’s prescriptions go to those age 17 and under, according to Glaxo. Ms. Meeker could not provide similar figures for Symbicort.

In 1994, Serevent was approved for sale, and the F.D.A. began receiving reports of deaths. A letter to the New England Journal of Medicine described two elderly patients who died holding Serevent inhalers. Glaxo warned patients that the medicine, unlike albuterol, does not work instantly and should not be used during an attack.

In 1996, Glaxo began a study of Serevent’s safety, but the company refused for years to report the results publicly. In 2001, the company introduced Advair, whose sales quickly cannibalized those of Serevent and then far surpassed them.

Finally in 2003, Glaxo reported the results of its Serevent study, which showed that those given the medicine were more likely to die than those given placebo inhalers. Glaxo said problems with the trial made its results impossible to interpret.

Asthma is caused when airways within the lungs spasm and swell, restricting the supply of oxygen. The two primary treatments are steroids, which reduce swelling, and beta agonists, which treat spasms. Rescue inhalers usually contain albuterol, which is a beta agonist with limited duration. Serevent and Foradil are both beta agonists but have a longer duration than albuterol and were intended to be taken daily to prevent attacks.

Advair contains Serevent and a steroid. Symbicort, introduced last year, contains Foradil and a steroid. In the first nine months of this year, Symbicort had $209 million in sales.

The problem with albuterol is that it seems to make patients’ lungs more vulnerable to severe attacks, which is why asthmatics are advised to use their rescue inhalers only when needed. The long-acting beta agonists may have the same risks.

But drug makers say this risk disappears when long-acting beta agonists are paired with steroids. The labels that accompany Serevent and Foradil instruct doctors to pair the medicines with an inhaled steroid.

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Antiasmaticos en el NYT

Warning Given on Use of 4 Popular Asthma Drugs, but Debate Remains

By GARDINER HARRIS

Published: December 5, 2008

WASHINGTON — Two federal drug officials have concluded that asthma sufferers risk death if they continue to use four hugely popular asthma drugs — Advair, Symbicort, Serevent and Foradil. But the officials’ views are not universally shared within the government.

The two officials, who work in the safety division of the Food and Drug Administration, wrote in an assessment on the agency’s Web site on Friday that asthma sufferers of all ages should no longer take the medicines. A third drug-safety official concluded that Advair and Symbicort could be used by adults but that all four drugs should no longer be used by people age 17 and under.

Dr. Badrul A. Chowdhury, director of the division of pulmonary and allergy products at the agency, cautioned in his own assessment that the risk of death associated with the drugs was small and that banning their use “would be an extreme approach” that could lead asthmatics to rely on other risky medications.

Once unheard of, public disagreements among agency experts have occurred on occasion in recent years. The agency is convening a committee of experts on Wednesday and Thursday to sort out the disagreement, which has divided not only the F.D.A. but also clinicians and experts for more than a decade.

Sudden deaths among asthmatics still clutching their inhalers have fed the debate. But trying to determine whether the deaths were caused by patients’ breathing problems or the inhalers has proved difficult.

The stakes for drug makers are high. Advair sales last year were $6.9 billion and may approach $8 billion this year, making the medication GlaxoSmithKline’s biggest seller and one of the biggest-selling drugs in the world. Glaxo also sells Serevent, which had $538 million in sales last year. Symbicort is made by AstraZeneca and Foradil by Novartis.

Whatever the committee’s decision, the drugs will almost certainly remain on the market because even the agency’s drug-safety officials concluded that they were useful in patients suffering from chronic obstructive pulmonary disease, nearly all of whom are elderly.

Dr. Katharine Knobil, global clinical vice president for Glaxo, dismissed the conclusions of the agency’s drug-safety division as “not supported by their own data.” Dr. Knobil said that Advair was safe and that Serevent was safe when used with a steroid.

Michele Meeker, a spokeswoman for AstraZeneca, said that the F.D.A.’s safety division improperly excluded most studies of Symbicort in its analysis, and that a review of all of the information shows that the drug does not increase the risks of death or hospitalization.

Dr. Daniel Frattarelli, a Detroit pediatrician and member of the American Academy of Pediatrics’s committee on drugs, said that he was treating children with Advair and that his committee had recently discussed the safety of the medicines.

“Most of us felt these were pretty good drugs,” Dr. Frattarelli said. “I’m really looking forward to hearing what the F.D.A. committee decides.”

About 9 percent of Advair’s prescriptions go to those age 17 and under, according to Glaxo. Ms. Meeker could not provide similar figures for Symbicort.

In 1994, Serevent was approved for sale, and the F.D.A. began receiving reports of deaths. A letter to the New England Journal of Medicine described two elderly patients who died holding Serevent inhalers. Glaxo warned patients that the medicine, unlike albuterol, does not work instantly and should not be used during an attack.

In 1996, Glaxo began a study of Serevent’s safety, but the company refused for years to report the results publicly. In 2001, the company introduced Advair, whose sales quickly cannibalized those of Serevent and then far surpassed them.

Finally in 2003, Glaxo reported the results of its Serevent study, which showed that those given the medicine were more likely to die than those given placebo inhalers. Glaxo said problems with the trial made its results impossible to interpret.

Asthma is caused when airways within the lungs spasm and swell, restricting the supply of oxygen. The two primary treatments are steroids, which reduce swelling, and beta agonists, which treat spasms. Rescue inhalers usually contain albuterol, which is a beta agonist with limited duration. Serevent and Foradil are both beta agonists but have a longer duration than albuterol and were intended to be taken daily to prevent attacks.

Advair contains Serevent and a steroid. Symbicort, introduced last year, contains Foradil and a steroid. In the first nine months of this year, Symbicort had $209 million in sales.

The problem with albuterol is that it seems to make patients’ lungs more vulnerable to severe attacks, which is why asthmatics are advised to use their rescue inhalers only when needed. The long-acting beta agonists may have the same risks.

But drug makers say this risk disappears when long-acting beta agonists are paired with steroids. The labels that accompany Serevent and Foradil instruct doctors to pair the medicines with an inhaled steroid.

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Anticolinergicos y eventos cardiovasculares

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Singh S, Loke YK, Furberg CD.

Department of Medicine, One Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. sosingh@wfubmc.edu

CONTEXT: Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. OBJECTIVE: To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. DATA SOURCES: Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers’ trial registries with no date restrictions. STUDY SELECTION: Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. DATA EXTRACTION: The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. DATA SYNTHESIS: After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.36]; P < .001, I(2) = 0%). CONCLUSION: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Enlace a Pubmed

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Anticolinergicos y eventos cardiovasculares

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Singh S, Loke YK, Furberg CD.

Department of Medicine, One Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. sosingh@wfubmc.edu

CONTEXT: Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. OBJECTIVE: To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. DATA SOURCES: Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers’ trial registries with no date restrictions. STUDY SELECTION: Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. DATA EXTRACTION: The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. DATA SYNTHESIS: After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.36]; P < .001, I(2) = 0%). CONCLUSION: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Enlace a Pubmed

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Fiebre, paracetamol y riesgo de asma, rinoconjuntivitis y eczema

Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme

Prof Richard Beasley DSc a , Tadd Clayton MSc b, Prof Julian CraneMBBS c, Prof Erika von Mutius MD d, Prof Christopher KW Lai DM e, ProfStephen Montefort PhD f and Alistair Stewart BSc g, for the ISAAC Phase Three Study Group
‡Members listed at end of paper

Summary

Background

Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6–7-year-old children from Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma.

Methods

As part of Phase Three of ISAAC, parents or guardians of children aged 6–7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the child’s first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression.

Findings

205 487 children aged 6–7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6–7 years (OR 1·46 [95% CI 1·36–1·56]). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1·61 [1·46–1·77] and 3·23 [2·91–3·60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6–7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema.

Interpretation

Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood.

Funding

The BUPA Foundation, the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the Hawke’s Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand, the New Zealand Lottery Board, Astra Zeneca New Zealand, and Glaxo Wellcome International Medical Affairs.

Affiliations

a. Medical Research Institute of New Zealand, Wellington, New Zealand
b. Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
c. Department of Medicine, Otago University Wellington, Wellington, New Zealand
d. Dr von Haunersches University Children’s Hospital, Ludwig-Maximilians University Munich, Germany
e. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, SAR China
f. Department of Medicine, University of Malta, Malta
g. School of Population Health, University of Auckland, Auckland, New Zealand

Correspondence to: Prof Richard Beasley, Medical Research Institute of New Zealand, PO Box 10055, Wellington 6143, New Zealand

http://feeds.feedburner.com/MedicinaGeneralYFamiliar

Fiebre, paracetamol y riesgo de asma, rinoconjuntivitis y eczema

Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme

Prof Richard Beasley DSc a , Tadd Clayton MSc b, Prof Julian CraneMBBS c, Prof Erika von Mutius MD d, Prof Christopher KW Lai DM e, ProfStephen Montefort PhD f and Alistair Stewart BSc g, for the ISAAC Phase Three Study Group
‡Members listed at end of paper

Summary

Background

Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6–7-year-old children from Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma.

Methods

As part of Phase Three of ISAAC, parents or guardians of children aged 6–7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the child’s first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression.

Findings

205 487 children aged 6–7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6–7 years (OR 1·46 [95% CI 1·36–1·56]). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1·61 [1·46–1·77] and 3·23 [2·91–3·60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6–7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema.

Interpretation

Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood.

Funding

The BUPA Foundation, the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the Hawke’s Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand, the New Zealand Lottery Board, Astra Zeneca New Zealand, and Glaxo Wellcome International Medical Affairs.

Affiliations

a. Medical Research Institute of New Zealand, Wellington, New Zealand
b. Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
c. Department of Medicine, Otago University Wellington, Wellington, New Zealand
d. Dr von Haunersches University Children’s Hospital, Ludwig-Maximilians University Munich, Germany
e. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, SAR China
f. Department of Medicine, University of Malta, Malta
g. School of Population Health, University of Auckland, Auckland, New Zealand

Correspondence to: Prof Richard Beasley, Medical Research Institute of New Zealand, PO Box 10055, Wellington 6143, New Zealand

http://feeds.feedburner.com/MedicinaGeneralYFamiliar

Selective Provision of Asthma Self-Management Tools to Families

Published online April 1, 2008
PEDIATRICS Vol. 121 No. 4 April 2008, pp. e900-e905 (doi:10.1542/peds.2007-1559)

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ARTICLE

Selective Provision of Asthma Self-Management Tools to Families

Michael D. Cabana, MD, MPH^a,b,c, D. Curt Chaffin, MD^d, Leah G. Jarlsberg^a, Shannon M. Thyne, MD^a and Noreen M. Clark, PhD^e

^a Department of Pediatrics
^b Department of Epidemiology and Biostatistics
^c Institute for Health Policy Studies, University of California, San Francisco, California
^d Division of Allergy, Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan
^e Center for Managing Chronic Disease, University of Michigan, Ann Arbor, Michigan

OBJECTIVE. Providing asthma education in a primary care setting can be challenging because of time and resource constraints. The purpose of this work was to determine factors associated with the provision of different asthma self-management tools.

METHODS. We conducted a cross-sectional survey with 896 parents of children with asthma (age 2–12 years). We collected information regarding demographics and asthma care, including parent receipt of an asthma action plan, a symptom diary, and asthma information materials; whether an asthma management plan was sent to the child’s school; and whether the physician reviewed written instructions on use of a metered-dose inhaler. We used multivariate logistic regression methods to determine factors associated with receipt of different asthma self-management tools controlling for demographic factors.

RESULTS. For families where parents only completed high school, there was greater likelihood of receipt of an asthma action plan and physician review of written instructions about how to use an inhaler. For families with a household income less than twice the poverty line, there was greater likelihood of receipt of an asthma action plan, the physician sending a letter to the child’s school regarding the child’s asthma, and receipt of an asthma symptom diary.

CONCLUSIONS. In our sample, primary care pediatricians do not routinely provide asthma education in accordance with National Heart, Lung, and Blood Institute asthma guidelines and “triage” which families receive additional asthma education. We believe that the use of targeted asthma education is a symptom of the limited time and competing demands during a typical visit. As a result, those involved in quality improvement need to help physicians become more efficient and effective at providing asthma education within such time constraints or develop alternative systems of providing asthma education.

Macrólidos para el asma crónica

Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG

Éste es el resumen de una revisión Cochrane traducida. La Colaboración Cochrane prepara y actualiza estas revisiones sistemáticas. El texto completo de la revisión traducida se publica en La Biblioteca Cochrane Plus (ISSN 1745-9990). De La Biblioteca Cochrane Plus, número 3, 2007. Oxford, Update Software Ltd. Todos los derechos están reservados.

Fecha de la modificación significativa más reciente: 06 de junio de 2005
Fecha de la traducción: 26 de febrero de 2007

Resumen

Antecedentes

El asma es una enfermedad crónica de las vías aéreas en la cual la inflamación de la mucosa respiratoria juega un papel fundamental. Los mecanismos responsables del mantenimiento de esta respuesta inflamatoria sólo se conocen parcialmente y existen pruebas de que la infección crónica por patógenos intracelulares (como la Chlamydia pneumoniae) puede jugar un papel. Los macrólidos son antibióticos con actividad tanto antimicrobiana como antiinflamatoria y su uso en pacientes asmáticos puede llevar a la reducción de la inflamación de las vías aéreas y por lo tanto mejorar los síntomas y la función pulmonar.

Objectivos

Determinar la eficacia de los macrólidos en el tratamiento de pacientes con asma crónica.

Estrategia de búsqueda

Se buscó en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Vías Respiratorias (Cochrane Airways Group) hasta mayo de 2005. Esta búsqueda también se complementó con búsquedas bibliográficas manuales de revisiones publicadas con anterioridad, actas de congresos, y contacto con los autores del estudio. En la búsqueda inicial, se incluyeron todos los idiomas.

Criterios de selección

Ensayos clínicos controlados, aleatorios que involucraran tanto a niños como a pacientes adultos con asma crónica tratados con macrólidos durante más de 4 semanas, versus placebo.

Recopilación y análisis de datos

Dos revisores examinaron de manera independiente todos los artículos identificados. Dos revisores revisaron de forma independiente los textos completos de los artículos potencialmente relevantes.

Resultados principales

Siete estudios que reclutaron un total de 416 participantes, cumplieron los criterios de inclusión. La calidad del informe de la metodología del estudio fue generalmente baja. Se evaluaron los hallazgos de los estudios que el tratamiento con macrólidos durante al menos 4 semanas en pacientes adultos y pediátricos tratados por asma crónica. Cuatro estudios revelaron un efecto positivo sobre los síntomas de los macrólidos en diferentes tipos de pacientes asmáticos. Hubo datos limitados disponibles para el metanálisis. No hubo diferencias significativas en el VEF1 para los ensayos paralelos o cruzados (crossover). Sin embargo, hubo diferencias significativas en la inflamación eosinofílica y en los síntomas. Un ensayo de grupos paralelos amplio informó diferencias significativas en el flujo máximo, pero estas diferencias se redujeron después de 6 meses de tratamiento.

Conclusiones de los revisores

Teniendo en cuenta el pequeño número de pacientes evaluado, no existen pruebas suficientes para apoyar o refutar el uso de los macrólidos en pacientes con asma crónica. Se necesitan estudios adicionales, en especial para aclarar el posible papel de los macrólidos en algunos subgrupos de asmáticos como aquellos con indicios de infección bacteriana crónica.

En las reagudizaciones del asma, el aumento de las dosis previas de corticoides inhalados no produce beneficio

 

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University of Michigan Department of Pediatrics Evidence-Based Pediatrics Web Site. Critically Appraised Topics (Temas Valorados Críticamente). Traducción autorizada.

Términos clave en inglés: glucocorticoids/therapeutic use; asthma/drug therapy; drug administration schedule
Términos clave en español: glucocorticoides: uso terapéutico;  asma:farmacoterapia;  esquema de medicación 

Fecha de recepción:  7 de noviembre de 2005
Fecha de aceptación: 12 de noviembre de 2005

Pregunta

En los niños con asma persistente que sufren una reagudización de su enfermedad, ¿se consigue reducir la gravedad de los síntomas incrementando sus dosis previas de corticoides inhalados?

Aspectos clínicos centrales en la valoración del problema:

1. En asmáticos en situación basal de asma persistente que experimentan una reagudización, el aumento al doble de la dosis de corticoides inhalados con que estaban siendo tratados, durante un periodo de tres días, no produjo diferencias estadísticamente significativas al valorar las cifras obtenidas en el registro de determinaciones matinales y vespertinas con medidores del PFE (Pico del Flujo Espiratorio).
2. Además, no se constataron diferencias significativas en ninguno de los apartados siguientes: cifras obtenidas en evaluaciones mediante escalas de puntuación clínicas para síntomas del asma, valores obtenidos en las mediciones espirométricas, valoración del grado de satisfacción de los padres o vigilancia para la aparición de efectos adversos.

Resumen de las claves encontradas revisando las evidencias disponibles:

1. El estudio seleccionado es un ensayo clínico controlado, aleatorizado, con doble cegamiento y grupo placebo, en el que se estudiaron 28 niños, con edades comprendidas entre 6 y 14 años y diagnóstico de asma persistente, leve o moderado. En este estudio, estos niños recibían tratamiento utilizando, durante los tres primeros días de la exacerbación de la enfermedad, una de las dos siguientes variedades de actuación, con respecto al uso de corticoides inhalados:
   • Incremento de las dosis previas de corticoides inhalados al doble.
   • Mantenimiento de las dosis basales de corticoides inhalados, añadiendo un placebo mediante dispositivo inhalador adecuado1.
2. Criterios de exclusión utilizados en el estudio: La utilización de corticoides orales, beta agonistas de acción prolongada, cromoglicato, historia de ingreso en UCI, ingreso reciente, cambios en las dosis de corticoides inhalados en los dos meses previos al inicio del estudio.
3. Los niños fueron estratificados por edad y sexo y posteriormente se distribuyeron, de forma aleatoria, en grupos. A cada uno de los grupos se le aplicaba una de las siguientes dos distintas secuencias de actuación posibles en sucesivas exacerbaciones que experimentasen:
   • Placebo inicialmente y después corticoides.
   • Corticoides la primera vez y posteriormente placebo.
4. Los parámetros de medición del resultado principal investigado en el estudio incluían: determinaciones del PFE, registrando las cifras matinales y vespertinas; evaluaciones mediante escalas de medición de la gravedad de la sintomatología del asma; valores de la espirometría; grado de satisfacción de los padres y registro de los efectos adversos.
5. La metodología del estudio se consideró válida si los pacientes se asignaron de forma aleatoria, si fueron seguidos hasta el final, si hubo cegamiento de los investigadores y si los grupos del estudio se trataron de la misma manera.
6. Al comparar el grupo basal con el grupo que recibió un aumento de corticoides no se encontraron diferencias estadísticamente significativas (p<0,05) en ninguno de los parámetros del estudio. En total se incluyeron 18 pares de exacerbaciones de asma.

Comentarios adicionales:

• Existen tres estudios que evalúan la eficacia de los corticoides inhalados frente a placebo para el tratamiento de las crisis del asma en niños que previamente no estaban recibiendo corticoides inhalados. En general, la administración de dosis altas de corticoides inhalados no disminuye la necesidad de administración de corticoides por vía oral, ni tampoco la necesidad de hospitalización2.
• En un estudio, de Connett y Lenney, se constató un descenso significativo de las sibilancias, pero no se encontraban diferencias en la tos, en el uso de broncodilatadores ni en la duración de los síntomas.
• Wilson y Silverman encontraron que las puntuaciones en escalas clínicas del asma, fueron significativamente más bajas en el grupo de tratamiento con corticoides inhalados.
• Svedmyr informó de cifras del PFE significativamente más altas (104% frente a un valor esperado del 96%), pero sin encontrar diferencias en la sintomatología.
• Existen diversos estudios, tanto en niños como en adultos, que demuestran una eficacia similar en el uso de corticoides orales o inhalados. Sin embargo, en estos estudios se utilizaron dosis elevadas de corticoides inhalados, por lo que se plantea la posible explicación de que el efecto valorado pudiera en realidad ser el resultado de la actuación sistémica del medicamento tras su absorción2.
• Los efectos secundarios de los corticoides inhalados son mínimos. En un estudio, realizado por el Childhood Asthma Management Program Group, se estudiaron estos efectos, causados por la administración de esteroides inhalados y observaron que tenía lugar un descenso en el crecimiento de 1,1 cm menos en la medición de la talla al final del estudio. Sin embargo, no se afectaba la talla final estimada, la edad ósea o los estadios de Tanner3.

Bibliografía:

1. Garrett J, Williams S, Wong C, Holdaway D. Treatment of acute asthmatic exacerbations with an increased dose of inhaled steoid. Arch Dis Child. 1998; 79: 12-17.
2. Hendeles L, Sherman J. Are inhaled corticosteroids effective for acute exacerbations of asthma in children. J Pediatr. 2003; 142: S26-S33.
3. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000; 343: 1054-63.

Autor de este CAT: Jim Connelly, MD Evaluador de este CAT: John Frohna, MD Fecha de la evaluación: 25 de mayo de 2005 Última actualización: 25 de mayo de 2005 URL del original en ingles disponible en: http://www.med.umich.edu/pediatrics/ebm/cats/asthmainh.htm . Department of Pediatrics and Communicable Diseases © 1998-2002 University of Michigan Health System

Autor de la traducción: Domingo Barroso Espadero. CS de Don Benito (Badajoz). pediatria@eresmas.net  

Como citar este artículo

Barroso D. En las reagudizaciones del asma,  el aumento de las dosis previas de corticoides inhalados no produce beneficio. Evid Pediatr. 2005; 1: 11.Traducción autorizada de: Connelly J.Increased Doses of Inhaled Steroids During an Asthma Exacerbation Show No Benefit. University of Michigan. Department of Pediatrics. Evidence-Based Pediatrics Web Site [en línea] [fecha de actualización: 25-V-2005; fecha de consulta: 3-X-2005]. Disponible en: http://www.med.umich.edu/pediatrics/ebm/cats/asthmainh.htm

Budesonide – Formoterol

Title	Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.
Comments	Erratum in: Eur Respir J. 2003 May;21(5):912.
Authors	Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H
Source	The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology
Date of publication	2003 Jan
Volume	21
Issue	1
Pages	74-81
Abstract	The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo, budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In a 12-month, randomised, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 yrs, mean forced expiratory volume in one second (FEV1) 36% predicted normal), patients received two inhalations twice daily of either budesonide/formoterol (Symbicort) 160/4.5 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg or placebo. Severe exacerbations and FEV1 (primary variables), peak expiratory flow (PEF), COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta2-agonist and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. FEV1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day 1 versus placebo and budesonide; after 1 week, morning PEF was improved versus placebo, budesonide and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta2-agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease.
Medical Subject Headings (MeSH)	Administration, Inhalation; Adrenal Cortex Hormones[administration & dosage][*therapeutic use]; Adrenergic beta-Agonists[administration & dosage][therapeutic use]; Budesonide[administration & dosage][*therapeutic use]; Double-Blind Method; Drug Combinations; Ethanolamines[administration & dosage][*therapeutic use]; Forced Expiratory Volume; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive[*drug therapy]; Time Factors Mesh check words: Female; Humans; Male; Middle Aged
Correspondence address	Dept Lung Diseases, Voivodeship Specialist Hospital, Radom, Poland.
Accession number	PUBMED  12570112
Publication type	Clinical Trial; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov’t
Cochrane code	SR-AIRWAYS
ID	CN-00435216
CLIB_SPECIFIC___________	EFFICACY AND SAFETY OF BUDESONIDEFORMOTEROL IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

En las reagudizaciones del asma, el aumento de las dosis previas de corticoides inhalados no produce beneficio

 

Artículos relacionados en EvidPediatr

PubMed sobre este tema

Scholar sobre este tema

Artículo en pdf

Versión para imprimir

Buscar:
autor:
claves:
Búsqueda avanzada

University of Michigan Department of Pediatrics Evidence-Based Pediatrics Web Site. Critically Appraised Topics (Temas Valorados Críticamente). Traducción autorizada.

Términos clave en inglés: glucocorticoids/therapeutic use; asthma/drug therapy; drug administration schedule
Términos clave en español: glucocorticoides: uso terapéutico;  asma:farmacoterapia;  esquema de medicación 

Fecha de recepción:  7 de noviembre de 2005
Fecha de aceptación: 12 de noviembre de 2005

Pregunta

En los niños con asma persistente que sufren una reagudización de su enfermedad, ¿se consigue reducir la gravedad de los síntomas incrementando sus dosis previas de corticoides inhalados?

Aspectos clínicos centrales en la valoración del problema:

1. En asmáticos en situación basal de asma persistente que experimentan una reagudización, el aumento al doble de la dosis de corticoides inhalados con que estaban siendo tratados, durante un periodo de tres días, no produjo diferencias estadísticamente significativas al valorar las cifras obtenidas en el registro de determinaciones matinales y vespertinas con medidores del PFE (Pico del Flujo Espiratorio).
2. Además, no se constataron diferencias significativas en ninguno de los apartados siguientes: cifras obtenidas en evaluaciones mediante escalas de puntuación clínicas para síntomas del asma, valores obtenidos en las mediciones espirométricas, valoración del grado de satisfacción de los padres o vigilancia para la aparición de efectos adversos.

Resumen de las claves encontradas revisando las evidencias disponibles:

1. El estudio seleccionado es un ensayo clínico controlado, aleatorizado, con doble cegamiento y grupo placebo, en el que se estudiaron 28 niños, con edades comprendidas entre 6 y 14 años y diagnóstico de asma persistente, leve o moderado. En este estudio, estos niños recibían tratamiento utilizando, durante los tres primeros días de la exacerbación de la enfermedad, una de las dos siguientes variedades de actuación, con respecto al uso de corticoides inhalados:
   • Incremento de las dosis previas de corticoides inhalados al doble.
   • Mantenimiento de las dosis basales de corticoides inhalados, añadiendo un placebo mediante dispositivo inhalador adecuado1.
2. Criterios de exclusión utilizados en el estudio: La utilización de corticoides orales, beta agonistas de acción prolongada, cromoglicato, historia de ingreso en UCI, ingreso reciente, cambios en las dosis de corticoides inhalados en los dos meses previos al inicio del estudio.
3. Los niños fueron estratificados por edad y sexo y posteriormente se distribuyeron, de forma aleatoria, en grupos. A cada uno de los grupos se le aplicaba una de las siguientes dos distintas secuencias de actuación posibles en sucesivas exacerbaciones que experimentasen:
   • Placebo inicialmente y después corticoides.
   • Corticoides la primera vez y posteriormente placebo.
4. Los parámetros de medición del resultado principal investigado en el estudio incluían: determinaciones del PFE, registrando las cifras matinales y vespertinas; evaluaciones mediante escalas de medición de la gravedad de la sintomatología del asma; valores de la espirometría; grado de satisfacción de los padres y registro de los efectos adversos.
5. La metodología del estudio se consideró válida si los pacientes se asignaron de forma aleatoria, si fueron seguidos hasta el final, si hubo cegamiento de los investigadores y si los grupos del estudio se trataron de la misma manera.
6. Al comparar el grupo basal con el grupo que recibió un aumento de corticoides no se encontraron diferencias estadísticamente significativas (p<0,05) en ninguno de los parámetros del estudio. En total se incluyeron 18 pares de exacerbaciones de asma.

Comentarios adicionales:

• Existen tres estudios que evalúan la eficacia de los corticoides inhalados frente a placebo para el tratamiento de las crisis del asma en niños que previamente no estaban recibiendo corticoides inhalados. En general, la administración de dosis altas de corticoides inhalados no disminuye la necesidad de administración de corticoides por vía oral, ni tampoco la necesidad de hospitalización2.
• En un estudio, de Connett y Lenney, se constató un descenso significativo de las sibilancias, pero no se encontraban diferencias en la tos, en el uso de broncodilatadores ni en la duración de los síntomas.
• Wilson y Silverman encontraron que las puntuaciones en escalas clínicas del asma, fueron significativamente más bajas en el grupo de tratamiento con corticoides inhalados.
• Svedmyr informó de cifras del PFE significativamente más altas (104% frente a un valor esperado del 96%), pero sin encontrar diferencias en la sintomatología.
• Existen diversos estudios, tanto en niños como en adultos, que demuestran una eficacia similar en el uso de corticoides orales o inhalados. Sin embargo, en estos estudios se utilizaron dosis elevadas de corticoides inhalados, por lo que se plantea la posible explicación de que el efecto valorado pudiera en realidad ser el resultado de la actuación sistémica del medicamento tras su absorción2.
• Los efectos secundarios de los corticoides inhalados son mínimos. En un estudio, realizado por el Childhood Asthma Management Program Group, se estudiaron estos efectos, causados por la administración de esteroides inhalados y observaron que tenía lugar un descenso en el crecimiento de 1,1 cm menos en la medición de la talla al final del estudio. Sin embargo, no se afectaba la talla final estimada, la edad ósea o los estadios de Tanner3.

Bibliografía:

1. Garrett J, Williams S, Wong C, Holdaway D. Treatment of acute asthmatic exacerbations with an increased dose of inhaled steoid. Arch Dis Child. 1998; 79: 12-17.
2. Hendeles L, Sherman J. Are inhaled corticosteroids effective for acute exacerbations of asthma in children. J Pediatr. 2003; 142: S26-S33.
3. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000; 343: 1054-63.

Autor de este CAT: Jim Connelly, MD Evaluador de este CAT: John Frohna, MD Fecha de la evaluación: 25 de mayo de 2005 Última actualización: 25 de mayo de 2005 URL del original en ingles disponible en: http://www.med.umich.edu/pediatrics/ebm/cats/asthmainh.htm . Department of Pediatrics and Communicable Diseases © 1998-2002 University of Michigan Health System

Autor de la traducción: Domingo Barroso Espadero. CS de Don Benito (Badajoz). pediatria@eresmas.net  

Como citar este artículo

Barroso D. En las reagudizaciones del asma,  el aumento de las dosis previas de corticoides inhalados no produce beneficio. Evid Pediatr. 2005; 1: 11.Traducción autorizada de: Connelly J.Increased Doses of Inhaled Steroids During an Asthma Exacerbation Show No Benefit. University of Michigan. Department of Pediatrics. Evidence-Based Pediatrics Web Site [en línea] [fecha de actualización: 25-V-2005; fecha de consulta: 3-X-2005]. Disponible en: http://www.med.umich.edu/pediatrics/ebm/cats/asthmainh.htm

Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children

EBM Reviews – Cochrane Database of Systematic Reviews Ducharme, FM. Di Salvio, F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. [Systematic Review] Cochrane Airways Group Cochrane Database of Systematic Reviews. 4, 2007.
AN: 00075320-100000000-01734

Background

Anti-leukotrienes agents are currently being studied as alternative first line agents to inhaled corticosteroids in mild to moderate chronic asthma.

Objectives

To compare the safety and efficacy of anti-leukotriene agents with inhaled glucocorticoids (ICS) and to determine the dose-equivalence of anti-leukotrienes to daily dose of ICS.

Search strategy

We searched MEDLINE (1966 to Aug 2003), EMBASE (1980 to Aug 2003), CINAHL (1982 to Aug 2003), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (August 2003), abstract books, and reference lists of review articles and trials. We contacted colleagues and international headquarters of anti-leukotrienes producers.

Selection criteria

Randomised controlled trials that compared anti-leukotrienes with inhaled corticosteroids during a minimal 30-day intervention period in asthmatic patients aged 2 years and older.

Data collection and analysis

Two reviewers independently assessed the methodological quality or trials and extracted trial data. The primary outcome was the rate of exacerbations requiring systemic corticosteroids. Secondary outcomes included lung function, indices of chronic asthma control, adverse effects and withdrawal rates.

Main results

27 trials (including 1 trial testing two protocols) met the inclusion criteria; 13 were of high methodological quality; 20 are published in full-text. All trials pertained to patients with mild to moderate persistent asthma. Only 3 trials focused on children and adolescents. Trial duration varied from 4 to 37 weeks. In most trials, daily dose of ICS was 400 mcg of beclomethasone or equivalent. Patients treated with anti-leukotrienes were 65% more likely to suffer an exacerbation requiring systemic steroids [Relative Risk 1.65; 95% Confidence Interval (CI) 1.36 to 2.00]. Twenty six (95% CI: 17 to 47) patients must be treated with anti-leukotrienes instead of inhaled corticosteroids to cause one extra exacerbation. Significant differences favouring ICS were noted in secondary outcomes where the improvement in FEV1 reached 130 mL [13 trials; 95% CI: 50, 140 mL]. Other significant benefits of ICS were seen for symptoms, nocturnal awakenings, rescue medication use, symptom-free days, and quality of life. Anti-leukotriene therapy was associated with 160% increased risk of withdrawals due to poor asthma control. Twenty nine (95% CI 20 to 48) patients must be treated with anti-leukotrienes instead of inhaled corticosteroids to cause one extra withdrawal due to poor control. Risk of side effects was not different between groups.

Authors’ conclusions

Inhaled steroids at a dose of 400 mcg/day of beclomethasone or equivalent are more effective than anti-leukotriene agents given in the usual licensed doses. The exact dose-equivalence of anti-leukotriene agents in mcg of ICS remains to be determined. Inhaled glucocorticoids should remain the first line monotherapy for persistent asthma

 

Estudio SMART: salmeterol y asma A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol Harold S. Nelson, MD; Scott T. Weiss, MD, MS; Eugene R. Bleecker, MD; Steven W. Yancey, MS; Paul M. Dorinsky, MD; the SMART Study Group * From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; Brigham and Women’s Hospital and Harvard Medical School (Dr. Weiss), Boston, MA; Wake Forest University School of Medicine (Dr. Bleecker), Winston Salem, NC; and GlaxoSmithKline (Mr. Yancey and Dr. Dorinsky), Research Triangle Park, NC.More… Correspondence to: Paul M. Dorinsky, MD, GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC 27709; e-mail: paul.m.dorinsky@gsk.com Abstract Study objective: To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. Design: A 28-week, randomized, double-blind, placebo-controlled, observational study. Setting: Study subjects were seen once in the study physician’s office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. Participants: Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting ß2-agonist use were excluded. Interventions: Salmeterol, 42 µg bid via metered-dose inhaler (MDI), and placebo bid via MDI. Measurements and results: Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo. Conclusions: For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown. Estudio SMART: The Salmeterol Multicenter Asthma Research Trial

The Salmeterol Multicenter Asthma Research Trial

A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol

Harold S. Nelson, MD; Scott T. Weiss, MD, MS; Eugene R. Bleecker, MD; Steven W. Yancey, MS; Paul M. Dorinsky, MD; the SMART Study Group

^* From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; Brigham and Women’s Hospital and Harvard Medical School (Dr. Weiss), Boston, MA; Wake Forest University School of Medicine (Dr. Bleecker), Winston Salem, NC; and GlaxoSmithKline (Mr. Yancey and Dr. Dorinsky), Research Triangle Park, NC.

Estudio SMART: salmeterol y asma A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol Harold S. Nelson, MD; Scott T. Weiss, MD, MS; Eugene R. Bleecker, MD; Steven W. Yancey, MS; Paul M. Dorinsky, MD; the SMART Study Group * From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; Brigham and Women’s Hospital and Harvard Medical School (Dr. Weiss), Boston, MA; Wake Forest University School of Medicine (Dr. Bleecker), Winston Salem, NC; and GlaxoSmithKline (Mr. Yancey and Dr. Dorinsky), Research Triangle Park, NC.More… Correspondence to: Paul M. Dorinsky, MD, GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC 27709; e-mail: paul.m.dorinsky@gsk.com Abstract Study objective: To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. Design: A 28-week, randomized, double-blind, placebo-controlled, observational study. Setting: Study subjects were seen once in the study physician’s office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. Participants: Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting ß2-agonist use were excluded. Interventions: Salmeterol, 42 µg bid via metered-dose inhaler (MDI), and placebo bid via MDI. Measurements and results: Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo. Conclusions: For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown. Estudio SMART: The Salmeterol Multicenter Asthma Research Trial

The Salmeterol Multicenter Asthma Research Trial

A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol

Harold S. Nelson, MD; Scott T. Weiss, MD, MS; Eugene R. Bleecker, MD; Steven W. Yancey, MS; Paul M. Dorinsky, MD; the SMART Study Group

^* From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; Brigham and Women’s Hospital and Harvard Medical School (Dr. Weiss), Boston, MA; Wake Forest University School of Medicine (Dr. Bleecker), Winston Salem, NC; and GlaxoSmithKline (Mr. Yancey and Dr. Dorinsky), Research Triangle Park, NC.

Estudio SMART: opinion del Instituto Catalan de Farmacologia

El analisis de dicho estudio por el ICF puede ser visto en http://www.icf.uab.es/WebsietesDB/shortcut.asp?refid=75959

National Asthma Guidelines Updated

National Asthma Guidelines Updated
BETHESDA, MD — September 5, 2007 — The National Asthma Education and Prevention Program (NAEPP) issued the first comprehensive update in a decade of clinical guidelines for the diagnosis and management of asthma. The guidelines emphasize the importance of asthma control and introduce new approaches for monitoring asthma. Updated recommendations …Full Stor

Tratamientos del asma Basados en la Evidencia

“No existe ningún problema, por complicado que sea, que cuando se analiza adecuadamente, no se complique más aún”.
A. Koestler

Tratamientos del asma Basados en la Evidencia

Dr. D. Pere Casan Clará.
Departamento de Pneumología. Hospital de la Santa Creu i de Sant Pau. Departament de Medicina.
Facultat de Medicina. U. A. B. Barcelona.

Cualquiera que se enfrente a las cuestiones que plantea el actual modelo de la “Medicina Basada en la Evidencia”, tiene la impresión de que está analizando el mismo problema de siempre, con nuevas herramientas, y no necesariamente con las que, de manera definitiva, le permitirán hallar la mejor solución y con el menor coste. Ocurre que el planteamiento es muy racional y pedagógico, pero las soluciones no siempre están fácilmente al alcance de la mano. La actual sociedad del bienestar busca constantemente cómo adaptarse a su modelo de vida, pero va dejando marginados al lado del camino. Marginados en temas materiales y en cuestiones intelectuales, que no son capaces de seguir la enorme velocidad con que se producen los cambios. Cada nuevo modelo precisa de nuevos lenguajes y, en términos de comprensión y diálogo, abundan los analfabetos. Pero dudar es avanzar y mientras dudemos podremos experimentar nuevas maneras de diagnosticar y tratar a nuestros enfermos. Y ya saben, mientras existan enfermos, habrá necesidad de que alguien los atienda. Sin embargo, conviene no perder de vista las palabras de Arthur Koestler, por si en algún momento hubiésemos creído que se trata de la piedra filosofal.

 

Guías, consensos, reconocimientos y normativas

Con el estado actual de los conocimientos y con la gran facilidad con que la información se difunde, podemos afirmar con un mínimo error a equivocarnos, que un paciente asmático puede ser tratado actualmente de forma muy parecida en cualquier parte del mundo. La única salvedad la constituyen la capacidades económicas, que impiden que la información (también mercancía de coste y consumo) llegue a los rincones donde el dinero no puede costearla.

Las grandes sociedades médicas mundiales han realizado un esfuerzo considerable para consensuar y aceptar procedimientos comunes, para tratar el asma de una forma muy parecida y asequible a todos los pacientes. En honor a la verdad hay que decir que el esfuerzo se aprecia, especialmente en la forma como los pacientes asmáticos vienen de su enfermedad, aunque no siempre este hecho vaya acompañado de un descenso en la prevalencia o en la gravedad de la enfermedad, variables que parece circulan por otros caminos.

Fruto de este impulso son la publicación de guías, recomendaciones y