Download Salmeterol vs. Combination Therapy

Salmeterol vs. Combination Therapy
Replacement/Addition to the List
Peer Feedback:
“salmeterol/fluticasone or formoterol/budesonide or formoterol/mometasone - the danger with
salmeterol alone if the risk of not coupling this drug with an inhaled corticosteroids, which has
been associated with an increased risk of death.”
“Symbicort (budesonide and formoterol) - I think you need a combination puffer for asthma, again
for the compliance issues”
Note: Second suggestion was made as an addition.
Literature Review Question:
Do combination medications have better compliance and outcomes then salmeterol
independently?
Literature Search:
Cochrane Review (2013, 2012)
eCPS - Respiratory Disorders: Asthma in Adults
Pubmed – “salmeterol AND ((Salmeterol AND fluticasone) or (Formoterol AND budesonide) or
(Formoterol AND mometasone)) AND (adherence OR compliance)”; “laba AND asthma AND
adverse AND review”
References taken from SMART 2011
Cochrane Review 2013 (Combined vs ICS)
A total of 15 studies of good methodological quality met the inclusion criteria by randomly
assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most
plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination
therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone.
The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21
exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be
reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality
was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N =
7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this
study was removed, no significant mortality difference was noted. The reduction in exacerbations
did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR
0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination
treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements
in health-related quality of life were measured on the St George’s Respiratory Questionnaire
(SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically
important difference. Adverse event profiles were similar between the two treatments arms, and
rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported
in earlier trials.
Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone,
especially for reduction in exacerbations. This review does not support the use of ICS alone when
LABAs are available. Adverse events were not significantly different between treatments. Further
long-term assessments using practical outcomes of current and new 24-hour LABAs will help
determine their efficacy and safety. For robust comparisons as to their relative effects, long-term
head-to-head comparisons are needed.
Nannini, Luis Javier, et al. "Combined corticosteroid and long‐acting beta2‐agonist in one inhaler
versus inhaled corticosteroids alone for chronic obstructive pulmonary disease." The Cochrane
Library (2013).
Safety of LABAs in Asthma (2012)
Concerns about the safety of long-acting b2-agonist (LABA) therapy, has led to the appearance
of multiple publications and recommendations. This review critically examines the available
clinical evidence and safety requirements for LABA use. An appropriate clinical study would
require an extremely large sample, making it impractical.
Based mainly on the safety concerns arising from the SNS and SMART5 6 studies, some authors
have suggested withdrawing LABA use for asthma therapy. However, these serious events have
been infrequent and appeared when LABAs were used as monotherapy. By contrast, evidence
from RCTs, meta-analysis of RCTs and observational studies, although limited by low statistical
power, have indicated that the use of combination therapy (LABAs plus ICS) is associated with a
decreased risk of serious asthma-related events. This is particularly true when the concomitant
use of LABAs plus ICS can be reasonably assured (combined in a single inhaler). Therefore, the
use of separate inhalers could result in periods of LABA monotherapy because of poor
compliance with ICS use. Combination therapy could reduce asthma mortality by increasing the
prescription and increasing compliance with ICS in the community. Furthermore, combination
therapy should be applied to all patients with moderate to severe asthma, and not just paediatric
and adolescent patients, as suggested by the FDA guidelines.
Rodrigo, Gustavo J., and José A. Castro-Rodríguez. "Safety of long-acting β agonists for the treatment of asthma: clearing the
air." Thorax 67.4 (2012): 342-349.
Cochrane Review 2012 (Combined vs LABA)
There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were
lower in comparison to those with LABA alone, from nine studies which randomised 9921
participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per
person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our
confidence in this effect was limited by statistical heterogeneity between the results of the studies
(I2 = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed
as the number of people experiencing one or more exacerbations over the course of the study,
FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6
studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one
year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation.
Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this
effect from high to moderate.
There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to
1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency).
There was no significant difference in mortality between people on combined inhalers and those
on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to
moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in
people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95%
CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an
annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were
no significant differences between the results for either exacerbations or pneumonia from trials
adding different doses or types of inhaled corticosteroid.
ICS/LABA was more effective than LABA alone in improving health-related quality of life
measured by the St George’s Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units
lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF),
rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and
forced expiratory volume in one second (FEV1) (70 mL higher with FPS, 50 mL higher with BDF).
Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with
FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as
the results were very inconsistent.
Nannini, Luis Javier, Toby J. Lasserson, and Phillippa Poole. "Combined corticosteroid and long‐acting
beta2‐agonist in one inhaler versus long‐acting beta2‐agonists for chronic obstructive pulmonary
disease." The Cochrane Library (2012).
SMART (2011)
Adherence to regular inhaled corticosteroid regimens is often poor, with only 15–20% of those
people deemed to need such drugs actually using them regularly.8 The importance of using
inhaled corticosteroids correctly needs to be discussed with patients by all those involved in the
care of their asthma.
Many patients will benefit more from the addition of a LABA than from increasing the
corticosteroid dose,3,9 but there has also been a safety concern that LABAs used without
concurrent inhaled corticosteroids in patients with asthma (an unlicensed use) may be associated
with an increased risk of death from asthma.10 Consequently, both the Medicines and Healthcare
products Regulatory Agency and the National Institute for Health and Clinical Excellence have
recommended the use of combination inhalers to ensure that LABAs are only taken with an
inhaled corticosteroid.3 Furthermore, the BTS/SIGN guideline now states that “in clinical
practice…it is generally considered that combination inhalers aid compliance and also have the
advantage of guaranteeing that the long-acting β2 agonist is not taken without the inhaled
steroids”.3 However, the use of combination inhalers could limit flexibility of dosing when patients
need to have their treatment stepped up or down.
Reddel, Helen K., and Kwok Y. Yan. "Single maintenance and reliever therapy (SMART) of
asthma." Thorax 66.1 (2011): 86-87.
Regular use of ICS and Asthma Prevention (2002)
The implications of our results for the treatment of asthma are important. This study strongly
suggests that it is not the use—but the regular use—of inhaled corticosteroids that is essential to
the effectiveness of these drugs. In addition, this effectiveness is sustained in the long term as
long as the medications are taken regularly. This aspect of asthma management seems
especially important in view of suggestions that compliance with inhaled corticosteroids appears
to diminish over time on treatment.35 Our study indicates that few patients were actually
benefiting from these medications.
In our full cohort 22.3% of subjects had been dispensed inhaled corticosteroids sometime during
the year before the index date but only 3.8% used them regularly, while in the hospitalised cohort
34.7% were prescribed inhaled corticosteroids but only 7.5% used them regularly. Thus, only 15–
20% of users deemed to need these drugs use them regularly and draw the full benefit.
Recognising that this study spanned the period 1976–97 when the primary role of inhaled
corticosteroids was less emphasised, it nevertheless seems important to assess and monitor
these patterns of use. In addition, strategies such as targeting of patients at greatest risk for
exacerbations, patient education on the importance of regular treatment, and reassurance
concerning safety could help to ensure that the potential benefits suggested by clinical trials and
observational studies can be translated into benefits at the clinical and population level.
Suissa, S., P. Ernst, and A. Kezouh. "Regular use of inhaled corticosteroids and the long term
prevention of hospitalisation for asthma." Thorax 57.10 (2002): 880-884.
eCPS (2015)
Class
Beta2-adrenergic
Agonists, longacting
Drug
salmeterol
Serevent
Corticosteroid/LA budesonide/formotero
BA
l fumarate dihydrate
Combinations
Symbicort
Corticosteroid/LA fluticasone/salmeterol
BA
Combinations
Advair pMDI, Advair
Dose
Adverse
Effects
Comments
Cos
ta
Diskhaler 50 µg/blister:1 blister BID
Diskus 50 µg/inhalation:
1 inhalation BID
Nervousness,
tremor,
tachycardia,
palpitations.
Recommended only if confident
patient will use prescribed inhaled
corticosteroid as well. Combination
LABA/corticosteroid product
preferred.
Not for reliever therapy.
$$$
Maintenance therapy: DPI 100/6 µg
or200/6 µg: 1–2 inhalations daily–BID;
maximum 4 inhalations/day. May
temporarily increase to 4 inhalations
BID for worsening asthma
Maintenance and reliever therapy: 1–2
inhalations BID or 2 inhalations once
daily. Inhale 1 additional inhalation PRN
in response to symptoms; if symptoms
persist after a few min, an additional
dose should be taken; maximum 6
inhalations on any single occasion;
maximum 8 inhalations/day
Sore mouth,
sore throat,
dysphonia,
oral thrush
(can be
reduced by
rinsing mouth
or using
spacer).
Nervousness,
tremor,
tachycardia,
palpitations.
Bone densitometry is suggested in
patients who require high doses or
have risk factors for osteoporosis.
$$$
pMDI 125/25 µg or250/25 µg: 2 puffs
BID
Diskus 100/50 µg, 250/50 µg or 500/50
Patients with personal or family
history of glaucoma (and need
high-dose inhaled corticosteroids)
should have IOP checked soon
after starting therapy and
periodically thereafter.
Fixed-dose combination inhalers
are more convenient, enhance
adherence, ensure the patient
receives their inhaled corticosteroid
with their LABA, and are less
$$$
$
Class
Drug
Adverse
Effects
Dose
µg: 1 inhalation BID
Diskus
expensive than the individual
agents combined.
Not for reliever
therapy.
Corticosteroid/LA mometasone/formoter
BA
ol fumarate dihydrate
Combinations
Zenhale
Cos
ta
Comments
A disadvantage is a loss in dosing
flexibility.
pMDI 50/5 µg, 100/5 µg or200/5 µg: 2
puffs BID
$$$
Not for reliever
therapy.
Legend:
$ < $25
$$ $25–50
$$$ $50–75
$$$$ $75–100
$$$$$ $100–125
Respiratory Disorders: Asthma in Adults; David G. McCormack, MD, FRCPC, FCCP; Date of
revision: April 2015
Medication
salmeterol
Uses
asthma adjuvant,
nocturnal and
exercise
induced
Contraindications
(CI), drug
interactions (DI) or
cautions
DI: CYP 3A4 inhibitor
Increased deaths in
African-American
and children
Long
acting beta agonists
increases risk of
asthma related death
Adverse Effects
(common and
severe)
upper respiratory
tract infection,
inflammation,
pharyngitis,
hoarseness,
dysphonia, bronchitis,
cough, headache,
nausea, vomiting,
sinusitis,
musculoskeletal pain,
fever, dizziness
Initial dose; typical dose
MDI: 25mcg 2 puffs every
12 hours Diskus: 50mcg
inhaled every 12 hours
Monitoring