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Primary Care Corner with Geoffrey Modest MD: Errors in Inhaler Usage

13 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review looked at articles on patient inhaler technique over the past 40 years, finding that 1/3 of users had poor technique, and that number has not changed over these 4 decades (see Sanchis J. Chest 2016; 150(2): 394).

Details:

  • 144 articles from 1975-2014 reported on 54,354 subjects performing 59,584 observed tests of technique, from 31 countries around the world
  • 54 studies reported on asthma, 14 on COPD, and 76 on both or unspecified.
  • Mean age of adults was 54, and of children was 9.

Results for most frequent errors:

  • Metered-dose inhalers (MDI): problems with full expiration in 48%, coordination 45%, speed and/or depth of inspiration 44%, and no postinhalation breath-hold in the 5-10 second range 46%
  • Breath-activated MDIs: problems with full expiration in 32%, speed and/or depth of inspiration 33%, and no postinhalation breath-hold 39%
  • MDI plus inhalation chambers: problems with preparation/shaking in 33%; exhale/seal chamber 34%; actuate/slow deep breath/breath-hold 38%
  • Dry-powder inhalers (DPI): problems with full expiration in 46%; postinhalation breath-holding 37%; preparing the inhaler 29%
  • The overall prevalence of correct technique was 31%; of acceptable, 41%; and of poor, 31%.
  • There were no significant differences between incorrect inhaler usage comparing the first and second 20-year periods of scrutiny

Commentary:

  • These results were actually better than I expected (this may be because these were from studies, where the patients may have received more rigorous training than in many offices or health centers). Even my patients who are smokers and used to inhaling and holding their breaths some (even those who smoke marijuana) mostly do terribly with inhalers.
  • MDIs had the worst outcomes, even if adding holding chambers (though there were pretty few studies on this, and there is lots of variability in sizes and functions of these chambers)
  • There were more limited studies on kids: mostly for MDI with inhalation chambers, and the children tended to do better: adults with errors in the 34-49% range, kids in the 21-31% range
  • There are a few other studies suggesting that correctly used MDIs are as beneficial as nebulizers, but i do have several patients who just can’t use their inhalers correctly despite education/review. So in some, nebulizers do work better…
  • The bottom line: inadequate technique in using inhalers is really common, apparently with all types of inhalers but worse with MDIs and without much improvement with inhalation chambers or over time. It makes sense to me that we have the patient regularly bring in their inhalers to their appointments and that we review their usage.

Primary Care Corner with Geoffrey Modest MD: COPD – Superiority of LABA and LAMA Combo Treatment

1 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A recently released report, presented at the American Thoracic Society, found that patients with COPD benefited more from the combination of a long-acting b-agonist (LABA) plus a long-acting anti-muscarinic (LAMA), as opposed to a LABA plus inhaled steroid (see DOI: 10.1056/NEJMoa1516385). Details of the FLAME trial (drug company sponsored trial), a double-blind, double-dummy, parallel-group, non-inferiority trial:

  • 3354 patients with COPD, from 356 centers in 43 countries. Inclusion criteria: >40 yo, grade 2 or greater in modified MRC dyspnea scale (patient describing shortness of breath as “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”), post-bronchodilator FEV1 25-60% of predicted value with FEV1/FVC <70%, and documentation of at least one COPD exacerbation in past year prescribed either systemic steroids, antibiotics or both
  • Mean age 65, 76% male, 78% white/most of rest Asian, duration of COPD 7 years, 56% on inhaled steroids, 40% current smokers, predicted post-bronchodilator FEV1 44%, post-bronchodilator FEV1/FVC 42%
  • GOLD stage:24% Group B (low risk/high symptom burden), 75% Group D (high risk/high symptom burden)
  • Assigned to LABA-LAMA combination (indacaterol 110 mg plus glycopyrronium 50 mg) once daily, vs LABA-steroid (salmeterol 50 mg plus fluticasone 500 mg) bid, followed 52 weeks.
  • Results, comparing LABA-LAMA to LABA-steroid:
    • >99% adherence to each of the treatment groups
    • Rate of COPD exacerbations: 3.59 vs 4.03, 11% lower [RR 0.89 (0.83-0.96, p=0.003]
    • Longer time to first exacerbation: 71 vs 51 days [HR 0.84 (0.78-0.91, p<0.001]
    • Rate of moderate or severe exacerbations: 0.98 vs 1.19, 17% lower [RR 0.83 (0.75-0.91, p<0.001], as well as time to the first severe exacerbation
    • The effect of LABA-LAMA was independent of baseline blood eosinophil count (comparing >2% vs <2%)
    • Subgroup analysis: all showed superiority for LABA-LAMA, though some did not reach statistical significance. Subgroups included race, smoking status at screening, severity of airflow limitation, severity of COPD (where those with high risk/high symptoms had the most improvement), number of COPD exacerbations in past year, or type of med use at screening for study)
    • Change from baseline throughFEV1 was 62 ml more in the LABA-LAMA group at week 52 (p<0.001), and the standard area under the curve for FEV1 was 110 ml more (p<0.001)
    • There was a small but not clinically significant improvement in the patients’ perception of their health status with LABA-LAMA, as measured by the St George’s Respiratory Questionnaire
    • There was a decrease in the use of rescue medications in the LABA-LAMA group
    • Incidence of adverse events was similar, though incidence of pneumonia was 3.2% with LABA-LAMA vs 4.8% LABA-steroid (p=0.02). Rates of discontinuation of treatment were 16.6% in LABA-LAMA and 19.0% with LABA-steroids

So, this trial showed actual superiority of the LABA-LAMA combination, not just non-inferiority

  • The combination LABA-LAMA was approved by the FDA last year, under the brand name: ultibro. (Neither drug nor price are available yet, though it may be cheaper to use the individual combo of tiotropium, a tried-and-true LAMA, with salmeterol or formoterol)
  • Prior trials have shown rough equivalence of tiotropium (a LAMA) by itself and the combination LABA-steroid for prevention of COPD exacerbations, leading to the GOLD guidelines recommending either of these therapies. Also, another study found that a LAMA-LABA combination was superior to a LAMA alone.
  • There are some data suggesting that the LABA-steroid combo works better in those with high blood eosinophil counts. The FLAME study, however, found that even in this subgroup (examined prospectively in the trial) still found superiority of LABA-LAMA

So, this study will change my practice, and for a few reasons. My prior approach for those with symptomatic COPD was to use a LAMA first (specifically tiotropium). If that were insufficient, I added a combo LABA-steroid med. Now, I will still start with tiotropium, but now add a LABA as a single agent, if clinically necessary (though, I should note, no study compares LABA-LAMA to triple therapy with LABA-LAMA-steroid, though I will reserve this triple hit as my third string). And I am concerned about the consistent association of inhaled steroids with pneumonia, as was also the case in this trial and the last blog I sent (see http://blogs.bmj.com/ebm/2016/05/17/primary-care-corner-with-geoffrey-modest-md-copd-safety-of-labas/, the SUMMIT trial, which demonstrated the safety of giving a LABA as sole treatment for COPD). And, the FLAME trial showed superiority for the LABA-LAMA is many realms: decreasing COPD exacerbations in those with even severe COPD as well as decreasing the time to a first exacerbation, improving some parameters of lung function (e.g. FEV1), improving (though not to the point of clinical significance) the patients’ perception of their health status, and a trend to overall fewer adverse events (and actually lower pneumonia events).

Primary Care Corner with Geoffrey Modest MD: COPD – Safety of LABAs

17 May, 16 | by EBM

By Dr. Geoffrey Modest

The recent SUMMIT study assessed the efficacy of combination steroid plus long acting b-agonist (LABA) therapy in patients with COPD, specifically looking at survival in those at high cardiovascular risk (see Vestbo J. Lancet 2016; 387: 1817), finding no increased mortality. A drug company sponsored study.

Details:

  • 16,485 patients 40-80 yo from 1368 centers in 43 countries, with cardiovascular disease (CVD) or at high risk of CVD, and post-bronchodilator FEV1 of 50-70% of predicted. Also at least 10 pack-years of smoking and modified MRC dyspnea scale of at least 2 (patient describing shortness of breath as: “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”
  • Mean age 65, 25% women, 81% white/17% Asian, BMI 28, 47% current smokers, post-bronchodilator predicted FEV1 60% (with 8% reversibility by the bronchodilator), 16% on pre-study anticholinergic, 34% on LABA, and 33% on steroid inhaler, 60% without COPD exacerbation in prior year/25% with one episode, 51% with CAD, 20% PAD, 10% stroke, 17% prior MI, 9% diabetes, 90% hypertension, 66% hyperlipidemia, 56% on antithrombotic, 67% lipid lowering med, 70% RAAS antagonist, 34% b -blocker). So, overall, 71% had established cardiovascular disease or diabetes, and 28% were at high risk. All inhaled steroids or long-acting bronchodilators (which would include anticholinergics) were stopped prior to the study
  • Randomized to: placebo, fluticasone 100 mcg, the LABA vilanterol 25mcg, or the combo. All once a day. Followed 1.8 yrs (max 4 yrs)

Results:

  • Medication adherence was high: 97% were taking >80% of prescribed meds
  • Primary outcome (all-cause mortality): 1037 deaths—not statistically different between groups, but varying from 6.7% on placebo to 6.0% on combo therapy. Mortality overall by diagnosis –Cardiovasc: 3.0% (43% of the total); pulmonary: 0.9% (13% of total); 1.5% cancer (23% of total)
  • Secondary outcome: composite of cardiovascular events (cardiovasc deaths, MI, stroke, unstable angina, TIA): no significant difference
  • Secondary outcome: on-treatment decline in FEV1: combo therapy reduced the decline (38 ml/year, vs 46 ml/yr on placebo, similar results with fluticasone, but no diff between LABA and placebo
  • Very small numbers of COPD exacerbations, but significant differences in annual rates with each active med over placebo [but pretty small absolute differences]:
    • Placebo: 0.35 for moderate and severe, and 0.07 for severe
    • Either single agent LABA or fluticasone: 0.31 and 0.06
    • Combo: 0.25 and 0.05
  • Adverse events. Not different between groups, including pneumonia

So, a few points:

  • I think this is an important study for several reasons:
    • The literature up till now has been pretty mixed on the question of overall or cardiovascular mortality in those with COPD specifically related to LABAs, though no definitive trial had looked at this outcome. The best study so far did find reduced cardiovascular and pulmonary mortality on a secondary analysis: the TORCH study (Calverly PM. NEJM 2007; 356: 775) assessed fluticasone 500mcg plus salmeterol 50 mcg twice daily (an 8-fold higher dose of steroid than in SUMMIT) and in patients with moderate to severe COPD but lower cardiovascular risk, finding an almost significant decrease in mortality (15.2% in placebo, 12.6% with combo therapy, an 18% decrease but p=0.052).
    • And, this CVD outcome is really important: not only do COPD and CVD have shared risk factors (e.g., smoking, air pollution, systemic inflammation, endothelial dysfunction, sedentary lifestyle), but those with moderate symptomatic COPD are more likely to die from CVD than any other cause (and in the SUMMIT study, 43% of deaths were attributed to CVD)
  • A few caveats:
    • Most of these patients in SUMMIT were pretty stable (e.g. COPD GOLD B), with only 15% having had a history of 2 or more exacerbations in the prior year
    • The study unfortunately did not allow baseline use of anticholinergics (e.g. tiotropium), which is the first line drug in COPD I have been using, given the prior mixed reviews on cardiac mortality with LABAs. [Though the 2013 GOLD recommendations do give equal weight to anticholinergic or LABA as first line (see Vestbo J. Am J Respir Crit Care Med 2013; 347)]
    • Though the combo steroid/LABA did increase statistically the FEV1 (and was clearly better than placebo), the difference was not clinically significant (only 8 ml/yr). On reviewing the decline of FEV1 over 3 years, the curves were really parallel (averaging a decline of about 40 ml) in all groups, suggesting that longer follow-up would be unlikely to further improve FEV1 In fact, the only real difference in the curves was that at the 90-day mark, where they based the initial assessment of FEV1 decline, there was an increase of around 40 ml in those with active treatment, so the measured decline was really based on an increase in the initial set-point, especially in the curves of patients on fluticasone.
    • It is difficult to compare the SUMMIT and TORCH trials, since in the latter, the patients had more severe COPD, were at lower CVD risk, but had much higher steroid dosing. The higher trend to increased survival in those in the TORCH study vs the SUMMIT study may well have been from the increased fluticasone dosing or other characteristics of the patient population. Perhaps the close-to-significant mortality benefit found in TORCH (which was equally spread through cardiovascular and pulmonary causes) would have been significant in a larger study such as SUMMIT, especially if the TORCH patients had higher CVD risk. But there was the likely trade-off of increased pneumonia rate/year in TORCH (0.07 vs 0.039 in SUMMIT) likely related to the higher steroid dose.
  • So, bottom line, SUMMIT was not a perfect study for COPD (since they did not use baseline tiotropium, and it was a very stable COPD  group with very few exacerbations). But it was very impressive that in this group with high cardiovascular risk, the combination of an inhaled steroid and LAB, or either individually, was not associated with increased mortality and specifically cardiovascular events (though, importantly, patients had moderately reasonable baseline CVD preventive meds). It was reassuring in this large study that there was no increase in pneumonia associated with the steroids, though they used a much lower dose than is often prescribed (100 mcg fluticasone). But the SUMMIT study does give more definitive and stronger support to using either LABA or anticholinergic as the first-line agent.

Primary Care Corner with Geoffrey Modest MD: Inhaled Steroids for COPD and Pneumonia

8 Dec, 15 | by EBM

By Dr. Geoffrey Modest

The data are pretty mixed on the efficacy of inhaled corticosteroids (ICS) in patients with COPD, yet in some studies 85% of COPD patients are on them. In this light, there is a recent large case-control study found that weaning some patients off ICS found a dramatic decrease in pneumonia cases !!! (See CHEST2015; 148(5): 1177).

Details:

  • Case-control study from Quebec, looking at a new-user cohort of patients with COPD (mean age 78.6, 50% male) put on ICS during 1990-2005, followed thru 2007 or until a serious pneumonia event (first hospitalization or death from pneumonia).
  • They compared those who discontinued ICS, vs those who continued, to assess development of a serious pneumonia event, adjusting for age, sex, comorbidities, and respiratory disease severity (which they defined as: number of prescriptions for b-agonists, ipratropium and tiotropium, theophylline, oral steroids, and antibiotics; and if there were hospitalizations with primary diagnosis of COPD; all measured in year before index date)

Results:

  • 103,386 users of ICS, of whom 14,020 had a serious pneumonia event during 4.9 yrs of follow-up (2.8/100/yr); those who developed pneumonia  were sicker overall (more COPD meds, antibiotics, COPD admissions, recent steroid use)
  • Discontinuation of ICS was associated with 37% decrease in serious pneumonia events [RR 0.63 (0.60-0.66)]
  • Risk reduction was rapid: 20% in first month to 50% by 4th month after discontinuation (the vast majority of benefit was in the first 3 months)
  • ​Risk reduction was most pronounced with stopping fluticasone [RR 0.58 (0.54-0.61)]; less with stopping budesonide [RR 0.87 (0.78-0.97)]

So, what does this all suggest?

  • Pneumonia may be a serious complication from continued ICS usage. There are other likely or known adverse effects, often related to suppression of the hypothalamic-pituitary axis: some ocular effects including cataracts and increased intraocular pressures, bone density may be adversely affected, and there are local problems with candida and irritation.
  • This is an observational study, so we really need a formal intervention study to show benefit of stopping ICS. But this study is really large and found quite dramatic differences in pneumonia, so should be taken seriously until a large enough intervention trial is done. There have been a couple of smaller trials done with unclear benefit of stopping ICS: the INSTEAD trial found an insignificant decrease in pneumonia in switching patients with moderate COPD from a combo long-acting b-agonist (LABA)/fluticasone to just a different LABA, but was a very small study with only 6-month follow-up. The WISDOM trial was larger with 2456 patients with moderate to severe COPD (GOLD 3-4 and at least one COPD exacerbation in past year), randomizing patients to step-wise decreases in fluticasone over 12 weeks vs continued use, and found no difference in COPD exacerbations in those off fluticasone, but they did find a pretty small 43 ml decrease in FEV1.0 at 52 weeks​ (see NEJM 2014 Oct 2;371:1285). There was again a non-significant decrease in pneumonia in those in the ICS withdrawal arm.
  • There has been a potential conceptual error that those who respond to oral steroids should respond to the less-toxic ICS, but there are no data to support this contention
  • My sense, and my clinical experience, does suggest that there are many patients, including some with very severe COPD, who do not respond to ICS. It is certainly appropriate to try ICS on patients with relatively frequent COPD exacerbations, or if inadequate symptom control with tiotropium augmented with LABA, but those who are pretty stable and without exacerbations probably should not be on them, and those on ICS without evident relief might deserve a trial of titrating them off ICS.
  • So, the benefit of ICS is hardly uniform (the individual studies have very mixed results), ICS do have potentially significant adverse effects, and, per the WISDOM trial, there does not seem to be major clinical problems by trying to wean people off them. But, nonetheless, many people even with stable mild to moderate COPD are taking ICS​.
  • Bottom line: it is probably not indicated to use ICS except if there seems to be an asthma component to the COPD,inadequate symptom control, or COPD exacerbations. But ICS are undoubtedly not required in all of the 50-85% of COPDers on them. And this study adds the potential for a very serious adverse event to the list of their complications. So, best to avoid them if possible and consider discontinuing them when the patient is stable to see how they do.

Primary Care Corner with Geoffrey Modest: New COPD guidelines more patient-centred

8 Aug, 13 | by EBM

the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has just come out with new guidelines (to see document summary, go to http://www.guideline.gov/content.aspx?id=43794.  The AHRQ (agency for healthcare research and quality) just promoted the new guidelines and provided a brief synthesis of the document. will also add the useful out-patient management reference (see http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf). in brief:

–COPD, a common and preventable/treatable disease, which is progressive and assoc with significant personal as well as social/economic consequences

–should be considered in anyone with dyspnea, chronic cough or sputum production and history of exposure to risk factors (cigarette smoke or other noxious particles such as smoke from biomass fuels — occup and environmental exposure)

–spirometry required to make dx, with post-bronchodilator FEV1.0/FVC <0.70, which is similar to recommendations by ACP/ACCP/ATS/ERS (am college physicians, am college of chest physicians, am thoracic society and european resp society)

–important to assess severity of disease including functional effects on patient (impact on health status, activities, etc), social supports, and risk of future events (exacerbations, admissions, death); also need to assess common comorbidities (cardiovasc, skeletal muscle dysfunction, metabolic synd, osteoporosis, depression, lung cancer) in overall assessment of specific patient.  important to know particulars of patient’s dz (timing/precipitants of exacerbations). and, ability to reduce exposures (smoking, environ/occup exposures). one validated tool to assess symptoms is the Modified British Medical Research Council (mMRC) questionnaire (see http://copd.about.com/od/copdbasics/a/MMRCdyspneascale.htm). GOLD also reinforces some older studies (there was one in the annals of internal medicine around 20 years ago) which find (not surprisingly) that, controlling for pack-yrs of cigarettes, people with COPD have higher risk of lung cancer (3-times higher in the annals study). unlike the ACP/ACCP/ATS/ER recommendations, GOLD does suggest that the following studies “be considered”: CXR, CT, diffusing capacity, a-1 antitrypsin, exercise testing — not so much to diagnose COPD but may be important in overall assessment of patient/significant comorbidities/treatment

–treatment: meds do not alter long-term decline of lung function (though: smoking cessation and removal of noxious exposures does help!!), but are important to decrease symptoms/reduce exacerbations. flu/pneumococcal vaccines important . meds: inhaled bronchodilators prn, they do note that “choice of b-agonists, anticholinergics, theophylline or combo therapy depends on individual patient’s response”. they comment on potential cardiac events with anticholinergics, but suggest that further studies are needed. inhaled steroids help (though no comment that the actual studies are really all over the map here: some with good response to steroids, some with none. i personally do try steroids early on in therapy, but stop them if no clinical benefit, since data do not suggest that steroids actually alter the natural history of COPD). moderate-to-severe COPD (FEV1.0<80% of predicted) may respond better to combo long-acting b-agonist (LABA) plus steroid, vs individual component. recent meta-anal showed decreased mortality with combo. some increased risk of pneumonia, though. some (meager) data that triple combo (LABA/steroid/tiotropium) is better (and i have many patients on this combo with apparent clinical improvement over double therapy). some likely further improvement with 15-20% dec in severe exacerbations in pts with poorly controlled chronic bronchitis by adding roflumilast to steroids, though i’m not aware of any data on the incremental effect of adding roflumilast to full triple therapy as above.they do not suggest routinely using antibiotics (eg azithro), mucolytics, antitussives (though i do occasionally use codeine-containing antitussive in patients who are unable to sleep because of cough), vasodilators.

–the GOLD management reference (see above)divides patients into 4 categories (analogous to asthma guidelines), with proposed treaments:

A= low risk less symptoms (<2 exacerb/yr, low mMRC of <2) — short acting b-agonist or anticholingeric   —  mMRC of 1 is “I only get breathless with strenuous exercise”.

 B= low risk more symptoms (<2 exacerb/yr, but mMRC>=2) — LABA or LA anticholinergic — mMRC of 2 is “On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace”

— C= high risk less sx (>=2 exacerb/yr with mMRC<2 — inhaled steroid plus LABA or LA anticholinergic

— D= high risk more sx (>=2 exacerb/yr with mMRC>=2) — inhaled steroid plus LABA and/or LA anticholinergic

GOLD more assertive in using combo therapies than previous guidelines

–pulm rehab (which we undoubtedly underuse in primary care). consider pulm rehab in anyone “who gets short of breath when walking on their own pace on level ground”.  improves exercise capacity, dec pt perception of breathlessness, improves health-related QoL, dec hospitalizations,dec anxiety/depression assoc with COPD, improves survival and recovery after hospitalization, improves response to LABAs. benefits extend beyond the immediate period of rehab. Note that this is a much more inclusive guideline than ACP/ACCP/ATS/ERS, which really pushes pulm rehab for symptomatic patients with FEV1.0<50%

–oxygen therapy (>15 hrs/d) in pts with severe resting hypoxemia (PaO2 <55mmHg or SaO2 <=88% with or without hypercapnea and confirmed twice over a 3 week period. unlike ACP/ACCP/ATS/ER, GOLD suggests oxygen therapy if PaO2=55-60 or SaO2 of 88% with evidence of pulmonary htn, periph edem or hct>55%

–recommendations for surgery (lung volume reduction, bullectomy, transplant) in selected patients (see paper for details)

–palliative care, end-of-life-care, hospice — should be discussed with patients given predicted pulmonary decline (again, undoubtedly not done enough by us guys)

–for acute exacerbations, antibiotics if evidence of: increased sputum purulence, increased sputum volume and increased dyspnea, esp in moderately to severely ill pts; or if 2 of these symptoms with one being increased sputum purulence, or anyone on mechanical ventillation.  for 5-10 days.

the biggest difference (to me) with previous guidelines is attention paid to patient-centered care — ie, we should not be treating FEV1.0’s (esp since they do not correlate so well with clinical disease), but look at the individual’s symptoms,  and risk of exacerbations.

i would add: i think it is really useful to know the specific clinical course of the individual patient, what their precipitants are to exacerbations, how bad are the exacerbations and historically what works for them.  early treatment is effective in preventing admissions/intubations. so, i have some patients with COPD who get more aggressive baseline treatment during the winter, if URIs are their usual precipitant. some patients with very severe COPD/many hospital admissions even get prednisone at home to take when they are beginning to get an exacerbation (i go through the indications for starting prednisone in detail with them) — and this has undoubtedly decreased admissions/intubations for some of them.

geoff

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