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Primary Care Corner with Geoffrey Modest MD: CPAP Does Not Reduce Cardiovasc Risk

3 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at patients with moderate-to-severe obstructive sleep apnea (OSA) and documented cardiovascular disease (CVD), finding no reduced risk of adverse cardiovascular outcomes by using CPAP (see DOI: 10.1056/NEJMoa1606599).

Details:

  • 2717 patients aged 45-75 who had moderate-to-severe OSA as well as coronary or cerebrovascular disease were randomized to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group)
  • Mean age 61, 81% male, 64% Asian/25% white, 51% with coronary artery disease/49% cerebrovascular disease, 79% hypertensive, 44% stroke, 33% MI, 30% diabetic, 15% smokers, 78% on BP meds/57% statins/75% aspirin/27% diabetic meds, BMI 29, apnea-hypopnea index (AHI) 29 (moderate-to-severe obstructive sleep apnea), 84% snoring almost every day, but minimal daytime sleepiness
  • Primary composite end point was: death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack
  • Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.
  • Results:
    • In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night (in beginning 4.4, decreasing to 3.5 hours/night by 12 months), and the mean AHI decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up, reflecting good control. 42% adhered to treatment for >4 hrs/night.
    • After a mean follow-up of 3.7 years:
      • Primary end-point event occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) [HR 1.10; (0.91 to 1.32) P = 0.34]. No significant effect on any individual or other composite cardiovascular end point was observed, and the trend was actually for more events in the CPAP group.
      • CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood, with greater reductions in anxiety and depression (25-30% lower). no difference in road-traffic accidents or accidents caused by injury
    • No difference in subgroups: region (China vs other), age, sex, severity of OSA, BMI, daytime sleepiness, type of CVD, diabetes.
    • There were differences in patient characteristics in those who used CPAP > vs < 4 hours/night: more were Caucasian/European, men, had baseline CAD, hypertension, and fewer had TIA/stroke. Using propensity-score matching, there were 86 events in the CPAP group and 98 in usual-care: non-significant (i.e., no benefit even in the subgroup who used CPAP for > 4 hours/night)

Commentary:

  • The indications for CPAP seem to continue to decrease over time. There is pretty good documentation that OSA is associated with hypoxemia and sympathetic stimulation, elevated blood pressure especially in the AM, inflammation, oxidative stress, metabolic syndrome/insulin resistance/type 2 diabetes (which seems to independent of the obesity common in both conditions), 2-3x increased risk of NAFLD (also apparently independent of obesity/diabetes), hypercoagulation, right-sided heart failure. There are several observational studies suggesting that there is an association with cardiovascular events (esp stroke). And there are studies finding that using CPAP lowers the blood pressure, but only a little (2-3 mmHg, but can be up to 6-7 mmHg in those with resistant hypertension, though a recent RCT found a 3-4mmHg decrease); and improves insulin sensitivity and endothelial function. And observational studies show that it lowers cardiovascular events in those adherent to treatment. Another study found a 64% relative and 28.5% absolute risk reduction in those using CPAP in a nonrandomized but prospective 6 year study, concluding “OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA” (see Buchner NJ. Am J CritCare Med 2007; 176 (12): 1274), advocating for more aggressive CPAP usage.
  • The concerns about CPAP are: that OSA is remarkably common, including 20-30% of males and 10-15% of females, though this depends on how OSA is defined and what the cutpoints are for the AHI (these percentages are if one uses an AHI>5/hour cutpoint); OSA seems to be much more common in those with underlying cardiovascular disease, cited at 40-60%; but CPAP is a pretty significant intervention (very difficult for many patients to use CPAP machines/uncomfortable, and in this study, the average was only 3.3 hours/night, which is similar to general clinical practice). Using CPAP therefore only makes sense if there is real clinical improvement.
  • A prior study was done in Spain (see Barbe F. JAMA 2012; 307(20): 2161) which randomized 357 patients to CPAP, 366 control. All patients had AHI of  >= 20/hr and no significant daytime symptoms; and they excluded anyone with prior cardiovascular event (i.e., much lower cardiovascular risk than those in the current study). In this 4-year study, as with the above study, there was no difference in cardiovascular events. Of note there was no difference in events when assessing those with the highest AHI levels or % of time with SaO2 <90%. Median CPAP usage was 5 hours, but those who used the CPAP >4 hours did have a 28% [HR 0-.72 (0.52-0.98), p=0.04)] lower incidence of hypertension or cardiovascular event. But looking specifically at cardiovascular events, there was a nonsignificant trend to lower CVD events (I should add here that 60% used the CPAP>4 hours, and this more adherent group may have done other healthy changes to decrease their risk of cardiovascular events. and these healthier things may have influenced the outcome more than the CPAP). Similarly if look at amount of time with SaO2<90%, the less time the fewer events.
  • So, overall, this current study showed very little cardiovascular benefit in many patients at high risk for CVD events and with pretty severe OSA. Although it is true that people used the CPAP only for 3-4 hours/night, this seems to be pretty much the range of usual CPAP usage, and they did find a dramatic decrease in AHI. My sense is that the indications for CPAP, a pretty significant and difficult intervention for many patients, have decreased considerably over time (early commentators suggesting that we should use it to prevent right-heart failure, or improve hypertension control, or decrease cardiovascular events/metabolic syndrome, etc.). Now, by far the major argument for CPAP for the vast majority of people, it seems to me, is for symptom control when patients are not sleeping well and having daytime somnolence or functional/psychological impairment(depression/anxiety, etc.) from inadequate sleep.

Primary Care Corner with Geoffrey Modest MD: Bronchiolitis guidelines for kids

28 Jan, 15 | by EBM

By: Dr. Geoffrey Modest

The American Academy of Pediatrics updated their 2006 guidelines on diagnosis and treatment of bronchiolitis In brief:

–For diagnosis: It’s all in the history and physical for both diagnosis and assessing disease severity — assess risk factors for severity (90%, chest PT, antibiotics (unless concomitant bacterial infection or strong suspicion). use nasogastric or IV fluids if infant cannot maintain hydration orally. Use pulse oximetry if clinically indicated.
–Give palivizumab in first year of life if hemodynamically significant heart disease or chronic lung disease of prematurity (eg 21% for at least the first 28 days of life). Give 5 monthly doses during RSV season.
–All people should disinfect hands before and after direct patient contact, use alcohol-based rubs for hand decontamination when taking care of kids with bronchiolitis, check on smoking exposure and counsel to avoid exposing the infant/child, encourage exclusive breast-feeding for first six months to decrease morbidity of respiratory infections.

So, the biggest change is to not use b-agonists/albuterol. Their recommendation is (it seems to me) a bit stronger than the data they reviewed — several meta-analyses found some improvement in symptom score (though this is noted by them to be observer dependent and may not be reliable). A few studies have looked at pulmonary function tests as an objective measure, and a couple of studies did not find any objective difference in infants in tidal breathing responses to albuterol​ — however, on looking further I found a recent Cochrane review on the subject of bronchodilators in infants with bronchiolitis (see DOI: 10.1002/14651858.CD001266.pub4.​10.1002/14651858.CD001266.pub4). I tried to look at the 3 specific PFT studies they cited from which they concluded there was no utility of albuterol , could only find 2, which had only 20 and 22 infants, one of which did find a statistically significant, but small and questionably clinically important improvement with albuterol, and one did not — the other study I could not find in PubMed or even the journal itself in the Harvard on-line library). In general, studies of albuterol have not found that they affect disease resolution, need for hospitalization, or length-of-stay in hospitals. And the guideline writers are concerned about cost and adverse effects (tachycardia, tremors). So, it seems that albuterol is unlikely to help most infants. But this does raise some questions. For example, we know that the correlation between PFTsand function in COPD and asthma is not great, so should we really consider this the objective gold standard in bronchiolitis (esp. when several meta-analyses have found some clinical improvement)? What about in kids with mild-to-moderate bronchiolitis? Effectively sending a very small infant away from the clinic and giving the parents nothing to treat them with may have some significant consequences: e.g, increased parental anxiety and increased likelihood of going to the emergency room. and, again, per the clinical guidelines: “several meta-analyses and systematic reviews [they cite 6] have shown that bronchodilators may improve clinical symptom scores”.​ Since the diagnosis of bronchiolitis is a clinical one, it is also likely that some of the kids have bronchospasm/reactive airway disease from a viral infection, which in fact may respond to b-agonists. All-in-all, in kids with mild to moderate bronchiolitis/wheezing, it seems that one could make a cogent argument to try albuterol and stop it if it is not working. So, I’m not so sure about this recommendation…..

Primary Care Corner with Geoffrey Modest MD: USPSTF Lung cancer screening revisited

24 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

There has been more chatter in the medical literature about the pluses and minuses of routine low-dose CT screening for lung cancer in smokers. Given that the USPSTF endorsed this, I decided to post again an old blog analyzing the study on which the recommendations were based (National Lung Screening Trial, NSLT) and critique of the recommendations, as below. A recent article in the NY Times (I believe) noted that Medicare would not cover until 2015, which is later than expected, suggesting they are rethinking this recommendation??? I added some specific issues with the recommendation:

  1. The USPSTF extended the recommendation from the age range of 55-74 in NSLT​to 55-80 year olds, presumably because of mathematical modeling.
  2. the USPSTF extended the interval of screening from 3 years in NSLT to all who smoked 30 pack-years and currently smoke or quit within the  past 15 years (i.e., with the potential that someone could get 25 annual LDCTs if they continued to smoke, with the attendant high dose follow-up scans in the large number who will have false positives), with the likelihood of creating additional cancers from radiation exposure (the NSLT was projected to create one cancer death per 2500 screened in just 3 years!!).
  3. The basis of the USPSTF extension of screening from 3 to up to 25 years was that in the 3 years of NSLT, they kept picking up new cancers. BUT, if you look at the year-by-year pickup, there was a pretty dramatic drop off by year 3 (goes from positive results of 27.3% in year 1 to 27.9% in year 2, then drops to 16.8% in year 3), which I think makes the potential 25 year annual screening suggestion a tad iffy…

___

This is from the Boston Globe today (December 2013):

Current cigarette smokers ages 55 to 80 who have smoked the equivalent of a pack a day for 30 years, or people who had those same smoking habits within the past 15 years, should be screened, advised the US Preventive Services Task Force, a group created by Congress. Under the federal health law, insurance companies will have to begin covering the $300 to $400 cost of the screening by the end of 2014.

 

Below is a review of the most important trial (National Lung Screening Trial):

Recent recommendations by the Am College of Chest Physicians to perform low-dose CT screening of smokers (see DOI: 10.1378/chest.12-2377). These recommendations parallel the interim recommendations of the American Lung Association.

Baseline: lung cancer is common and has generally poor prognosis (esp. with lesions greater than stage 1), causing as many deaths as the combo of the next four cancers. one thing to keep in mind is that there are newer therapies that work better than the old ones — targeted to the specific tumor-associated genetic mutations engendered by the cancer (i.e., possible that these new treatments could change the risk/benefit analysis of screening in the future).  of note, the arena of smoking-related morbidity is changing: tobacco companies have seen shrinking local markets (showing that sometimes after decades of obvious connection with lung cancer/persistent denial by the corporations, public health initiatives may work….); as a result, there has been huge-scale exporting (“dumping”) of cigarettes to developing nations, with likely huge increases in tobacco-related morbidity and mortality in the near future. [And, as an addition to this blog, a fundamental shift by the cigarette companies to focus on developing and advertising e-cigarettes]

Cancer prevention: attempts to prevent cancer in smokers mostly with different antioxidants or anti-inflammatories (e.g. b-carotene, aspirin, selenium, inhaled steroids, vitamin E, retinoids) have not panned out and are not recommended. preventing smoking initiation is the clearest prevention (though 15% of lung cancers are not smoking related. we do know, however,  from many epidemiologic studies over the decades that cancer risk geometrically increases with multiple insults, including air pollution/environmental exposures and occupational exposures in addition to smoking). for those who smoke,  smoking cessation clearly helps!, with about a 15 year lag to reducing the lung cancer risk to near non-smoker levels (unlike the heart disease risk, which decreases dramatically within 6 months of smoking cessation).

Screening methods: prior studies have not shown clinical benefit with either CXR of sputum cytology screening.

Low-dose CT screening (LDCT) has found lots of nodules identified in 10-50% of smokers. Here is the current LDCT study by the National Lung Screening Trial Research Team (NSLT)—(see DOI: 10.1056/NEJMoa1102873).

Details:

–screened 27K high risk patients with LDCT and 27K with CXR yearly for 3 years and followed another 3.5 yrs

— found 25% with positive screen on LDCT and 7% by CXR,

–lung cancer: 645 cases/100K person-yrs with LDCT and 572/100K person-yrs with CXR –13% more.

–most notably, there were 247 lung cancer deaths/100K person-yrs with LDCT and 309 lung cancer deaths/100K person-yrs with CXR, a significant 20% decrease (though not very large absolute numbers – difference of only 62 deaths/100K person-yrs…), and all-cause mortality decreased 7%.

–the LDCT pickup of cancer was similar each of the 3 years (suggesting that it would be useful to continue screening annually).

–but, very large number of false positives (>95% of positives were false ones). The vast majority of those with abnormal screens had follow-up radiologic procedures, a small minority with invasive testing (1.2% of pts not found to have cancer had a biopsy or bronchoscopy).

–BUT, given the high number of abnormal screens, the “low-dose” radiation did not remain so low. the LDCT delivered 1.5 mSv of radiation (vs 8 mSv for regular chest CT) because of the large number of positive LDCT who then received follow up chest CT or PET CT,  the average dose overall for the LDCT cohort was actually 8mSv. The rough calculation is that this degree of radiation exposure (mostly based on atomic bomb and some medical imaging studies) would create one cancer death per 2500 people screened.

 –the recommendation (from NSLT):  for smokers and former smokers aged 55-74 who have smoked >30 pack-yrs and either continue smoking or have stopped within the past 15 years should be offered annual LDCT, if comprehensive care can be provided as in the NLST trial.

 So, this recommendation, at this point, is by pulmonary specialist organizations, which may have some self-interest (organizationally, or by the individuals involved in crafting the recommendations) to be aggressive (e.g., as with the American urology assn and PSA screening).  We may want to wait for a more neutral group (e.g. USPSTF, though I suspect they will follow suit, given that the NLST is a well-done study). my fundamental concern is that at the same time we are getting recommendations about expensive, intensive, high-tech screening for a largely preventable cancer (and with a significant but low difference in absolute death rates by screening), we in the trenches are getting less and less support for programs to prevent or stop smoking (cutbacks in health educators, varying and variable insurance-based support for smoking cessation devices).  In addition, I am very concerned about the additional radiation exposure (will also resend some of my previous emails about risks of radiation exposure).

 

 

 

Primary Care Corner with Geoffrey Modest MD: Obstructive sleep apnea

20 Nov, 14 | by EBM

Sleep

The American College of Physicians (ACP) issued a clinical practice guideline in August (see doi:10.7326/M12-3187), which basically supports performing a sleep study for patients with unexplained daytime sleepiness. There are many adverse outcomes associated with sleep apnea (OSA), including cardiovascular disease (with the degree of risk associated with the degree of disordered breathing), hypertension, cognitive decline, metabolic abnormalities including type 2 diabetes, increased peri-operative mortality, all-cause mortality (esp. with higher levels of disordered breathing) etc. However, some clinicians have been ordering sleep studies in anticipation of improving these associated conditions, which is problematic both because of the remarkable baseline frequency of OSA in the population (on the order of 10-17%) which increases with age, and the data are lacking that finding OSA and treating it leads to any improvement in these associated conditions (e.g. CPAP does not reduce mortality or coronary heart disease in those without daytime sleepiness; there was small reduction in blood pressure in those with daytime sleepiness and using CPAP, but unclear if true in those who are asymptomatic).

The ACP’s specific recommendations:

— ACP recommends a sleep study for patients with unexplained daytime sleepiness (weak recommendation low-quality evidence)

— ACP recommends formal polysomnography in a sleep lab for diagnostic testing in patients suspected of OSA. they recommend portable sleep monitors in patients without serious comorbidities (e.g. chronic pulmonary disease, heart failure, neurologic disorders, where portable monitors have not been evaluated) as an alternative to polysomnography, when polysomnography is not available for diagnostic testing (weak recommendation, moderate-quality evidence). Studies are limited with direct comparisons between the different types of portable monitors, though it makes sense not to use ones that cannot differentiate between central and obstructive sleep apnea, since CPAP may be contraindicated if central. [Although ACP recommends home monitors “when polysomnography not available”, many insurers are requiring the home based monitors unless there are significant comorbidities.]

A couple of comments. First, I really agree with their conclusions. Lacking clear data on clinical benefit, we should be focusing the use of sleep studies on those with functional impairment which might be related to OSA and where CPAP does improve outcomes: i.e., those with daytime somnolence. In this regard it is important to keep in mind that, on the one hand, only 37% of patients with severe OSA had daytime somnolence, and on the other, mortality associated with severe sleep apnea is unrelated to daytime somnolence (but, again, intervention studies are lacking, with no difference in cardiovascular mortality, as noted above). Second, and most importantly, we should continue to focus our attention on the prevention and treatment of obesity, the best-documented risk factor for OSA (though, 15% of OSA diagnoses are in non-obese people –another study confirmed that 32% of men with documented OSA were non-obese with 11% having normal weight, and 12% of women were non-obese with 3% being of normal weight).

Geoff

Primary Care Corner with Geoffrey Modest MD: Placebo for coughs in kids, and an adult perspective

18 Nov, 14 | by EBM

An interesting article found that placebo was more effective than no treatment in kids with cough (see doi:10.1001/jamapediatrics.2014.1609). This was a 13 month study in 2 outpatient pediatric practices of kids aged 2-47 months who had nonspecific acute cough of less than 7 days. Parents were given surveys the day before and after the allotted treatment, which was either pasteurized agave nectar, caramel-colored placebo (each given 30 minutes prior to bedtime), or “no treatment”. All parents were instructed in routine care of the child: hydration, saline nasal spray, and use of acetaminophen/ibuprofen as needed (ie, the “no treatment” group did get treatment, just not a teaspoon of “meds”). The survey assessed cough frequency, cough severity, congestion severity, rhinorrhea severity and the cough effect on child and parent sleep.

Results:​

–119 children completed the study, mean age 23 months, 50% female, 87% white non-Hispanic.

–No difference in any of these outcomes between administering agave nectar or placebo (though agave nectar was nonsignificantly better on all outcomes)

–Significant differences between either one of these two treatments and “no treatment” for all of the above outcomes, all with p<0.05

–Subgroup analysis suggested that the effects of agave nectar over placebo were somewhat more pronounced in those under 1 year old, though nonsignificant (but only 30 kids <1yo)

Agave

So, background is that acute cough is a remarkably common outpatient complaint in kids and a common reason for a healthcare visit, with nocturnal cough disturbing sleep in 88% of children and 72% of parents. Given current valid concerns about adverse events with medications as well as their unclear efficacy in young children (eg antihistamines, decongestants, antitussives), providers have limited medication options. There are some studies showing efficacy of honey, but that should not be used in kids <1yo for concerns about botulism. in above study, they chose agave nectar, since it sort of tastes like honey (though no data that it really works), does have some anti-inflammatory properties (as does honey), but lacks honey’s anti-oxidant effects.​

So, this article does suggest that placebo has a role for cough in kids (there was an analysis in 2002 suggesting that 85% of the treatment response in adults with cough was attributable to placebo effect). This is really not so surprising. There is an obvious interconnection between an individual’s clinical condition and their psychosocial state. to me, perhaps the most obvious example is the therapeutic effect of the provider-patient relationship itself. Many patients derive tremendous benefit without specific treatment. There are a slew of articles on the placebo effect, showing both the dramatic efficacy of placebo, the relatively frequent adverse effects as well, and effect even studies where the patients benefited even if aware that they were taking a placebo. there was an interesting article I ran across last year on this but, one of my favorite articles in the medical literature was an analysis of the CHARM trial, a placebo controlled trial of candasartan in patients with congestive heart failure (see Lancet 2005; 366: 2005–11), which found that those patients who adhered well to their treatment did well and had a lower all-cause mortality, and it didn’t matter whether they were assigned to candasartan or to placebo — ie, people who took their assigned medicine (who were probably more open to having a good effect from that medicine and perhaps more open to “taking care of themselves”) had similarly lower mortality independent of whether their assignment was to “active” medication or not…..

Geoff

Primary Care Corner with Geoffrey Modest MD: Lung auscultation

25 Feb, 14 | by EBM

NEJM just came out with review article on lung auscultation (see doi: 10.1056/NEJMra1302901). it does seem that we are moving towards using echocardiograms instead of cardiac auscultation, bolstered by studies confirming that cardiologists ain’t so great at predicting whether a murmur is from the right or left side of the heart. and, seems that at the slightest hint of lung problems, CTs are the way to go. although i am being a tad sarcastic, my sense is that medical students/residents/perhaps some of the younger attendings are not as fluent as some of us more traditionally-trained ones (a euphemism for older ones….) so, will circulate this article. a few points:

–some of the nomenclature has evolved over the years. for better or worse, rales don’t exist anymore. just crackles. and “moist” vs “dry” is out (turns out that one person’s moist is another’s dry, and neither seemed to correlate with much), though there are fine vs coarse crackles (fine being short, heard mid-to-late inspiration, nonclearing with cough, and associated more with interstitial fibrosis, CHF, pneumonia; coarse being early inspiratory and throughout expiration, clear with cough and often related to secretions). and now there are “squawks”, with a short musical component/short wheeze, accompanied or preceded by crackles (signifying problem with distal airways, could be interstitial lung dz or pneumonia)
–their table is a good (xeroxable) one of the different sounds and where they come from/what they usually mean.
–and, just to show the value of auscultation, in a study of 386 workers exposed to asbestos, auscultation-detected crackles were 100% accurate in identifying asbestosis, i.e. as good as CT (they were obviously looking for it/listening with a focus, but pretty impressive anyway)

geoff

Primary Care Corner with Geoffrey Modest MD: Severe asthma treatment

18 Feb, 14 | by EBM

new guidelines (they just keep comin’…), this time on defn, eval and treatment of severe asthma (see doi: 10.1183/09031936.002020), put out by combo of European respiratory society and american thoracic society. main points:

definition: severe asthma (approx 5-10% of asthmatics) = asthma requiring high dose inhaled steroids (ICS) plus second controller (eg ICS plus long-acting b-agaonist (LABA) or leukotriene modifier/theophylline) for the past year and/or systemic steroids (>50% of the time in the past year) to control, or remains uncontrolled despite this therapy (uncontrolled = poor symptom control, or >=2 bursts of systemic steroids in past yr, or at least one hospitalization in past yr, or FEV1<80% after appropriate bronchodilator withhold.  only after confirm asthma dx — see evaluation section

[there is an extensive section on phenotyping asthmatic kids and adults, which seems to reflect age of onset, gender, severity, proneness to exacerbation, and presents some data on differentiating different phenotypes (eg, whether there is an inflam response, and if so, presence of eosinophils or neutrophils), and some info on different genetics (eg IL4 or IL6 pathways and receptors)/epigenetics.   pretty interesting stuff, which reinforces that asthma is a myriad of different conditions lumped together, and that this knowledge may ultimately determine different treatment approaches.  but, will leave this for you to pursue in the document, if interested]

evaluation:

1. make sure it is asthma (misdiagnosis as uncontrolled asthma found in 12-30%). evaluate sx, triggers, environmental/occup factors. one of common misdiagnoses is respiratory sx related to obesity. they have a table (Table 6) of diseases that can masquerade as asthma in kids (eg, vocal cord dysfunction, bronchiolitis, reflux/microaspiration, foreign body, etc), and in adults (vocal cord dysfunction, copd, panic attacks, chf, etc). pfts with and without bronchodilators (esp after withholding b-agonists) needed for diagnosis. they do recommend that a high resolution chest CT be done in kids and adults with severe asthma and atypical asthma presentation, eg rapid decline in lung function, lots of mucous, etc (low quality evidence).
2. assess comorbidities: nonadherence to rx is most common (32-56%) as cause of “severe asthma”, but comorbidities can make asthma worse (eg, rhinosinusitis, nasal polyps, obesity, smoking, OSA, aspirin, anxiety/depression, etc). GERD is included in list, though role is probably over-rated and anti-reflux rx not help so much.
3. there are some broad phenotypic aspects that can help. for example, those with early-onset allergic phenotype (may respond to anti-IL5 or anti-IL13 therapies), later onset obese phenotype (responds to weight loss more than obese, early onset asthma), late onset eosinophilic phenotype. they have a table (Table 9) with specifically targeted, mostly monoclonal antibody therapies for different phenotypes)

therapy:

1. there is often a relative ICS insensitivity, such that oral steroids are needed regularly (or IM triamcinolone), though there is less asthma responsiveness in those with obesity, smoking, low vitamin D levels, and non-eosinophilic (esp, it seems, in those with neutrophilic) asthma. there are some novel drugs in the wings for those with corticosteroid insensitivity
2. there are some people who do respond to high-dose ICS (eg fluticasone 500 mcg in kids, or >500 mcg in adults — their table 4 has the list), though in pts with moderate asthma, increasing to these doses is not effective
3. adding LABA to ICS is helpful, and is often more helpful than increasing ICS in patients with moderate asthma (those with severe asthma should already be on high dose ICS). I have posted prior studies showing that African-Americans in general are more likely to be resistant to the effects of b-agonists (short or long-acting), perhaps related to b-adrenoreceptor genotypes. anticholinergics (eg, ipratropium, tiotropium), though usually less helpful than b-agonists, may be very useful in people resistant to b-agonists, and can be added to ICS and LABA.
4. low dose theophylline can help (this sort of fell off the charts several years ago, was revived some with the COPD/GOLD guidelines, and I have found that it helps some people a lot, both with asthma and COPD)
5. they recommend treatment guided by clinical symptoms, though recommend sputum eosinophil counts done in experienced centers is helpful in adults (low quality evidence) but not in kids. they recommend against using FeNO (exhaled nitric oxide fraction) measurements. consider omalizumab in adults and kids (low qual evidence) if severe allergic (IgE-dependent) asthma, if not controlled on regular meds.  not use methotrexate, macrolide antibiotics (in spite of recent study in NEJM on azithromycin). only use antifungals if documented allergic bronchopulmonary aspergillosis (low quality evidence). bronchial thermoplasty may be useful (low quality evidence) in specialized sites. no suggestions about cromoglycates (cromolyn).

so, adds a little to the current approach. highlights importance of accurate diagnosis, including PFTs, and the approach to asthmatic phenotypes, which reinforces the conception of asthma as a variety of unrelated diseases with common clinical presentation, is useful and is opening the door to more specific targeted therapies.

geoff

 

Primary Care Corner with Geoffrey Modest MD: Antibiotics and ibuprofen (still) don’t help acute bronchitis

16 Oct, 13 | by EBM

recent online article in BMJ finding lack of efficacy of antibiotics or ibuprofen on acute bronchitis with discolored sputum (see BMJ 2013;347:f5762 doi: 10.1136/bmj.f5762). 416 adults aged 18-70 in primary care centers in spain with sx of respiratory tract infection of less than 1 week, cough predominant with discolored sputum, and at least one other sx suggesting lower resp tract infection (dyspnea, wheezing, chest discomfort or pain). chest xray not required to r/o pneumonia — the dx of acute bronchitis was a clinical one. randomized to ibuprofen 600 TID, amox/clavulanic acid 500/125 TID, or placebo for 10 days.  patients reported sx in diary. overall, 40% of patients were smokers, 10% had diabetes, 8% with fever, >50% had increased CRP with 25% quite high CRP (>21). results

 

–median # days from the initial presentation of frequent cough slightly decreased with ibuprofen (9 days) vs those on abx (11 days) or placebo (11 days), not statistically different

–no diff in probability of cough resolution

–adverse effects common with abx (12%), vs ibuprofen (5%) or placebo (3%).

 

so, not a lot to do for patients with acute bronchitis. (note: this does not apply to patients with copd and exacerbation with change in color of their sputum). cochrane reviews do not show benefit from b-agonists or anti-tussives. it is pretty clear that providers do prescribe antibiotics a lot for acute bronchitis (>60% of the time), and even more so if there is discolored sputum (3.2 times as likely as in patients without discolored sputum). would have been better in this study if they evaluated utility of antibiotics or ibuprofen in patient subgroups (eg, smokers, or diabetics, or those with higher CRP), but overall this article provides further impetus to avoid prescribing antibiotics, with their adverse effects on the patients and on society overall from resistant bacteria.

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

Universal screening with computed tomography for lung cancer? Finally a randomized trial…but what to do??

11 Jul, 11 | by EBM

Expert opinion and observational studies have favored lung cancer screening but trials (of plain xrays) have not shown benefit, until now. For years, many have been asking for a randomized trial. Now that the results of the (US) National Lung Screening Trial (NSLT) have been published, it reminds me of the admonition to “be careful what you ask for, you just might get it.”

The randomized trial compared three screenings, either low dose CT scans or plain chest radiographs and adherence to the screening protocol was >90%.  How to address a positive test was left to clinicians outside the trial. It enrolled 53 454 participants age 55-74, who smoked at least 30 pack-years currently or who had quit in the past 15 years, and had not had lung cancer or a recent chest CT scan, hemoptysis or unexplained weight loss. The authors estimate only 7% of US current or former smokers would meet these criteria. So the study results do NOT apply to 93% of smokers. One wonders though, to whom they will be applied (paying customers?).

What were the results? Amazingly, despite the publication source (New England Journal of Medicine, http://bit.ly/qKs6Lq) and widely agreed upon reporting guidelines, the main results are presented as relative reductions, making them seem large (a 20% decrease in death from lung cancer). I don’t mean to minimize though, just to be clear—it is important that there was a reduction, and more lung cancers were diagnosed in the (low dose) CT group, which had fewer lung cancer deaths. The absolute reduction was the difference between 356 lung cancer deaths in 144,103 person-years in the CT group and 443/143,368 in the plain x-ray group. The absolute risk of lung cancer death among those screened at least once was 1.3% in the CT group, 1.6% in the x-ray group, an absolute risk reduction of 0.312%, for a number needed to screen with 3 tests of 320 to prevent 1 lung cancer death over 7 years. Overall mortality was also reduced (by 0.5%). Complications of evaluation of a positive test were 1.4% in the CT group, 1.6% in the x-ray group.
The vast majority of positive tests were false positives (96% in the CT group, 95% in the x-ray group).

None of this addresses long term cumulative population harms from radiation exposure or any impact on likelihood of quitting smoking.

What to do? Many may reach different conclusions depending on the presentation of the results. Others will take these results and then add patient values and preferences. Others still may wish to wait to see the cost effectiveness analyses.

What will you do? You now have the evidence…

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