Kirthi Gunasekera MD Respiratory Physician National Hospital of Sri Lanka Colombo,

Transcription

1 Kirthi Gunasekera MD Respiratory Physician National Hospital of Sri Lanka Colombo,

2 BRONCHODILATORS: Beta Adrenoreceptor Agonists Actions Adrenoreceptor agonists have many of the same actions as epinephrine/adrenaline, the hormone of fright/flight/fight. Stimulate the beta2 receptors in the lungs. SABAs - used for decades as broncho dilators Acute and Chronic Asthma Good therapeutic profile

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4 Beta agonists-safety Concerns Concern about the safety of SABAs initially arose in the 1960s - marked increase in asthma-related deaths occurred in countries where isoprenaline was available. Then a second epidemic of asthma-related deaths occurred in New Zealand after inhaled fenoterol, a non-selective SABA, was introduced in In 1989, after safety warnings were issued in response to data from case-controlled studies implicating fenoterol, the death rate fell to 1.1 per 100,000 per year and further to less than 0.8 per 100,000 per year when the fenoterol was pulled from the market in 1990.

5 Inhaled beta agonists SALBUTAMOL SALMETEROL FORMETEROL 1960 s 1970 s 1980 s 1990 s INHALED ISOPRENALINE FENOTEROL 5

6 Long Acting Bronchodilators- Safety Concerns The role of long-acting beta-agonists (LABAs) in the treatment of asthma continues to be controversial. In the early 1990s, highly selective, third generation LABAs, salmeterol and formoterol were introduced. Considered a major advance in bronchodilator therapy improved lung function and QOL

7 GINA Guidelines

8 Long Acting Bronchodilators- Safety Concerns Reduce bronchodilator sensitivity to beta agonists Induction of tolerance to bronchoprotective effects Evidence for risk of increased morbidity and mortality if the symptom control achieved with LABA use led to a discontinuation of inhaled corticosteroid (ICS) therapy

9 Serevent Nationwide Surveillance (SNS) Study A 16-week, randomized controlled trial, with 25,180 patients in the UK -GSK compared twice daily salmeterol 50ug bd to albuterol 200ug four times daily. 70% on ICS concomitantly The frequency of asthma-related deaths was numerically ( 3 fold increase) but not significantly higher in the salmeterol group However,no increase in hospital admissions / Life threatening events The number of medical withdrawals because of asthma, which were fewer with salmeterol than with salbutamol

10 Serevent Nationwide Surveillance (SNS) Study Because the number of events was very small, was the difference is a chance finding. Bias may have been introduced by the higher proportion of withdrawals in the salbutamol group Finally, the authors considered that a number of deaths could have been prevented by more appropriate use of ICS.

11 Serevent Nationwide Surveillance (SNS) Study Variable Summary of data from the SNS study ( adapted from Castle et al) Salmeterol (n=16787) Salbutamol (n= 8393) Relative Risk (95% CI) Total deaths 54 (0.31%) 20 (0.24%) 1.35 (0.18 to 2.25) 0.25 p value Respiratory and asthma deaths 12 (0.07%) 2 (0.02%) 3.00 (0.67 to 13.4) Hospitalisations and life-threatening asthma 193 (1.1%) 102 (1.2) 0.95 (0.74 to 1.20) 0.74 Withdrawals due to asthma 488 (2.9%) 318 (3.8%) 0.77 (0.67 to 0.88)

12 LABA Adverse Effects The proposed mechanism by which LABAs may worsen asthma control is the down-regulation of the b-adrenergic system as a result of the stimulation of b-receptors. Certain polymorphisms of the human b 2 -adrenergic receptor gene have also been implicated. Asthmatics who are homozygous for the variant with an arginine at the 16 th amino-acid position of the b 2 -adrenergic receptor are at risk for decreased airflow and worsening asthma control when using b-agonists. It is estimated that this genotype occurs in one sixth of the U.S. population and may be more prevalent in certain ethnic groups, such as African-Americans.

13 This data prompted the large safety trial A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol: The Salmeterol Multicenter Asthma Research Trial SMART 2006 Volume 129:15-26 Harold S. Nelson, MD; Scott T. Weiss, MD, MS; Eugene R. Bleecker, MD; Steven W. Yancey, MS; Paul M. Dorinsky, MD; 13

14 SMART Study Design 28-week, multicenter, randomized, double-blind, placebocontrolled, observational surveillance trial initiated in June 1996 USA Target enrollment: ~60,000 patients Included patients >12 years with asthma currently using a prescription asthma medication No history of previous salmeterol or formoterol use assigned to receive either salmeterol 50 mg twice daily via metered-dose inhalers or placebo for 28 weeks in addition to their usual therapy. Nelson HS et al. Chest. 2006;129:15-26.

15 SMART Study Endpoints Primary Endpoint Combined respiratory-related deaths or lifethreatening experiences (intubation and ventilation) Key Secondary Endpoints Respiratory-related deaths Combined asthma-related deaths or lifethreatening experiences Asthma-related deaths Nelson HS et al. Chest. 2006;129:15-26.

16 Salmeterol Multicenter Asthma Research Trial Nelson et al, Chest 2006 Study Period = 28 Weeks Enrollment Placebo (n=13,179) Salmeterol (n=13,176) 3 Deaths 13 Deaths Planned Interim Analysis ~50% enrollment n = 25,000 n = 25,000 The higher rate of asthma-related deaths (RR = 4.37) in the Salmeterol group led to the study being halted prematurely

17 SMART Interim Analysis, 2002 SMART did not reach predetermined stopping criteria at the interim analysis Data Safety Monitoring Board recommended Timely completion (within 2 years) If this was not possible: Discontinuation of study and rapid dissemination of the interim results SMART was discontinued due to difficulties in enrollment and findings in African American patients Nelson HS et al. Chest. 2006;129: Data on file, GlaxoSmithKline.

18 SMART Results All Patients and Ethnic Subgroups 1 Endpoint Combined Respiratory-related Deaths or Life-threatening Experiences RR (95% CI) SAL n PLA n 1.40 (0.91, 2.14) (0.62, 1.76) (1.54, 10.90) Endpoints Respiratory-related Deaths Combined Asthma-related Deaths or Life-threatening Experiences Asthma-related Deaths Nelson HS et al. Chest. 2006;129: (1.06, 4.41) (0.94, 5.56) (0.83, 18.26) (1.01, 2.89) (0.55, 2.14) (1.68,14.45) (1.25, 15.34) (0.70, 48.37) (0.89, 58.94) 7 1 Total N=13,176 N=13,179 Caucasian N=9281 N=9361 African American N=2366 N=2319

19 SMART study: asthma-related deaths 19

20 SMART: Summary of Results Total Population For the primary endpoint, 50 events occurred in patients receiving salmeterol vs 36 events in those receiving placebo (RR=1.40, 95% CI [0.91, 2.14]) A significant increase in respiratory-related deaths was observed in patients receiving salmeterol vs those receiving placebo (RR=2.16, 95% CI [1.06, 4.41]) The number of combined asthma-related deaths or life-threatening experiences was 37 in patients receiving salmeterol vs 22 in those receiving placebo (RR=1.71, 95% CI [1.01, 2.89]) A significant increase in asthma-related deaths was observed in patients receiving salmeterol (13 of 13,176 pts) vs those receiving placebo (3 of 13,179 pts) (RR=4.37, 95% CI [1.24, 15.34])

21 SMART: Summary of Results African Americans For the primary endpoint, 20 events occurred in patients treated with salmeterol vs 5 in those treated with placebo (RR=4.10, 95% CI [1.54, 10.90]) A higher number of respiratory-related deaths (8 vs 2, RR=3.88, 95% CI [0.83, 18.26]) A higher number of combined asthma-related deaths or life-threatening experiences (19 vs 4, RR=4.92, 95% CI [1.68, 14.45]) A higher number of asthma-related deaths (7 vs 1, RR=7.26, 95% CI [0.89, 58.94])

22 SMART: Findings The data from SMART are not adequate to determine, nor was the study designed to determine, whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, modifies this risk of asthma-related death Given the similar mechanism of action of beta 2 -agonists, it is possible that the findings of SMART may represent a class effect

23 Long Acting Bronchodilators- Safety Concerns In August 2003 in response to this data, the FDA issued black-box safety warning labels indicating a small increased risk of asthma-related death from salmeterol use. in March 2006, tougher labeling changes to the blackbox warnings on salmeterol products were released, including the recommendation that salmeterol should only be used if other asthma drugs, such as inhaled corticosteroids, proved insufficient.

24 Is it a class effect? Fast onset Slow onset Short acting Salbutamol (oral salbutamol) Long acting Formoterol Salmeterol 24

25 Formoterol studies Clinical studies caused concern about a possible relationship between the use of higher doses (24 ug twice daily) and an increase in serious asthma Exacerbations. On FDA request, Novatis Phase 4 post marketing clinical trial which enrolled 2085 patients with stable mild-to moderate persistent asthma (64% received regular concomitant ICS), showed five (0.9% of all patients) severe asthma-related complications in the group receiving 24 ug formoterol compared with two (0.4%) in the 12 mg group, and only one (0.2%) in the placebo group, suggesting that formoterol 24 ug twice daily was associated with an increase in serious asthma exacerbations

26 Formoterol data Martinez NEJM (2005) 353:25;

27 FDA Meta - Analysis It explored possible associations of LABAs with asthma hospitalisations, intubations, and deaths. It was based on data from 110 randomised, parallel controlled clinical trials ( patients) that the sponsors submitted to the FDA Levenson M 2008

28 FDA Meta - Analysis Considered four products that contain a LABA and are approved in the USA for the treatment of asthma: salmeterol plus fluticasone, formoterol, salmeterol, and formoterol plus budesonide. The majority of patients (>70% of total sample) were from salmeterol trials. SMART provided a substantial percentage (43%) of the total sample. Trials with treatment durations of 12 weeks or more (94%).

29 FDA Meta - Analysis Overall, data showed that LABAs were associated with an increased risk difference (RD) of asthma-related events relative to non-laba treatment as measured by the asthma composite endpoint consisting of asthma deaths, asthma intubations, and asthma hospitalisations

30 Pooled risk difference (RD) with 95% CI of asthma endpoints in the US Food and drug Administration (FDA) meta-analysis (n, number of events; N, total sample; LABAs, longacting β2 agonists) (adapted from Levenson14). Rodrigo G J, Castro-Rodríguez J A Thorax 2012;67:

31 FDA Meta - Analysis Interestingly, RDs for the asthma composite endpoint only increased when LABAs without randomly assigned ICS were compared with non- LABA treatment In contrast, the comparison of LABAs with randomised ICS versus randomised ICS alone (same ICS and dose) was not statistically significant

32 FDA Meta - Analysis There was a general trend among age, with higher RD among the younger age groups. RDs for all age groups, except the 65 and over age group, were positive and statistically significant. Women and African Americans showed significant increases in RD.

33 FDA Meta - Analysis In summary, LABAs were associated with an increased risk of an asthma composite endpoint. Of 44 deaths and intubations in the LABA-exposed population, 43 occurred among patients (0.19%) in trials in which ICS use was not mandatory compared with one death among 7862 patients (0.01%) in trials with mandatory ICS therapy. No deaths or intubations were reported for patients treated with single-device combinations of ICS and LABAs.

34 Safety of long-acting β agonists for the treatment of asthma: clearing the air Thorax 2012;67: doi: /thx On the basis of nearly 20 systematic reviews and databases, the authors conclude that LABA monotherapy significantly increases the risk of asthma-related adverse effects. Use of LABAs concomitantly with inhaled corticosteroids (ICS) significantly reduces asthma hospitalisations and is not associated with lifethreatening events and asthma-related deaths, especially when concurrent use of LABAs and ICS can be reasonably assured (use of a single inhaler device).

35 Safety of LA-ß2 agonists SNS study published SMART begins Novartis s Foradil aerolizer approved for sale in US Unpublished Foradil data shows increase in serious asthma-related events November: FDA public health advisory on LABA safety Manuscript on LABA safety data, label changes Salmeterol approved for sale in US SMART protocol modified SMART halted July: FDA convenes advisory committee meeting on LABA safety December: F. Martinez article in NEJM

36 Cates CJ, Cates MJ, Lasserson TJ. Regular treatment with formoterol for chronicasthma: serious adverse events. Cochrane Database Syst Rev 2008; Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2008 Salpeter SR, Buckley NS, Ormiston TM, et al. Meta-analysis: effect of long-acting b-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006

37 The authors examined 16 meta analyses 3 compared LABA with placebo 8 compared LABA + ICS with ICS alone 3 presented both comparisons Additionallly they evaluated 2 databases of RCT s submitted by sposors to the FDA

38 Of the six reviews comparing LABAs with placebo four showed significant increases in asthma deaths in the LABA group, with one excess asthma death every LABA patients. The majority of deaths recorded in these reviews were from SMART

39 Reviews comparing LABAs plus ICS versus ICS alone showed quite a different picture Overall, asthma deaths and life threatening events were very rare, and patients treated with LABAs plus ICS presented a reduced risk of asthma hospitalisations

40 FDA 2010 NEW SAFETY REQUIREMENTS FOR LABAs 1. The use of LABAs without the use of an asthma controller medication such as an ICS is contraindicated (absolutely advised against) in the treatment of asthma 2. LABAs should only be used as additional therapy for patients with asthma who are currently taking a long-term asthma control medication, such as an ICS, but whose symptoms are not adequately controlled 3. LABAs should be used for the shortest period of time required to achieve control of asthma symptoms and then discontinued if possible, once asthma control is achieved; patients should then be maintained on asthma controller medication; 4. Paediatric and adolescent patients who require the addition of an LABA to an ICS should use a combination product containing both an ICS and a LABA to ensure adherence to both medications.

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42 Use of LABAs without ICS has been more common in COPD Treatment trials in COPD show greater benefit in symptom control and lung function is obtained from the long-acting anticholinergic bronchodilator, tiotropium, compared with either short-acting anticholinergics (ipratropium), or long-acting bronchodilators (salmeterol or formoterol).

43 COPD patients receiving tiotropium reported no benefit of addition of LABA or a combination ICS/LABA inhaler with respect to reduction of exacerbations-aaron et al = Ann Int Med 2007 Addition of LABA with ICS improved lung function and reduced hospitalizations, whereas LABA alone did not. Calverlery et al NEJM highlighted a significant risk of pneumonia in COPD population when exposed to ICS as monotherapy or ICS/LABA combination.

44 Despite beneficial effects on symptom relief and improved lung function, the reports of increased exacerbations and deaths are worrying. Concerns about mortality associated with use of LABAs in COPD have been highlighted More than a doubling of the risk of respiratory death in COPD with use of LABA vs placebo, and an almost double risk with LABA vs anticholinergic therapy - metaanalyses conducted by Salpeter and colleagues J Gen Int Med 2006

45 CHEST 2012Rodrigo and colleagues - safety of LABA in patients with COPD. Literature review, Mata analysis of 27 studies reports no increased risk in COPD patients of mortality with use of LABAs. LABA with ICS was associated with lower mortality compared with LABA without ICS (relative risk, 0.35; 95% confidence interval, 0.14 to 0.93; p = 0.03). Treatment with tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs consistent with previous data.

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