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Archive for October, 2016

Primary Care Corner with Geoffrey Modest MD: Glucometers Lower A1c’s in Non-Insulin Using Diabetics, a Little

31 Oct, 16 | by EBM

By Dr. Geoffrey Modest

BMJ just published a meta-analysis of randomized controlled trials (RCTs), finding that non-insulin using diabetic patients who self-monitored their blood sugars had improved glycemic control (see doi:10.1136/bmjopen-2015-010524 ). This analysis included several new studies, not available in prior reviews.

Details:

  • 15 RCTs were identified with 3383 patients
  • Results:
    • Those using SMBG (self-monitoring of blood glucose) had:
      • Lower HbA1c by −0.33 (−0.45 to −0.22); p<0.001 [the quality of evidence was rated as moderate]
      • Lower BMI by −0.65 (−1.18 to −0.12); p=0.02 [the quality of evidence was rated as low]
      • Lower total cholesterol (TC) by −0.12 (−0.20 to −0.04); p=0.003 [the quality of evidence was rated as high]
      • Lower waist circumference by -2.22 (-4.40 to -0.03); p=0.047 [no comment, but i assume that is in centimeters; the quality of evidence was rated as moderate]
      • No significant difference in fasting plasma glucose, systolic or diastolic BP, HDL, LDL, triglycerides, or weight
      • Subgroup analyses: no difference if Asian countries or US/Europe; A1C was improved in both short-term (<6 month, by -0.36%) or long-term studies (>12 month, by -0.28%). BMI and TC changes were only significant in the <6 month group. and though waist circumference was improved overall, it was not significantly improved in the subgroups, but was near-significant (p=0.06) only in the >12 month group (by -3.15); also similar A1C reductions were found in patient with newly diagnosed type 2 diabetes (T2DM) vs duration >12 months [no further analysis for really long-termers]; SMBG was significantly more effective in patients with lower A1C (<8%) vs higher
    • Adverse events: most common was the incidence of hypoglycemia (higher in SMBG group), though their rate (episodes/patient) was lower

Commentary:

  • Prior concern about SMBG reflect its high cost (21% of diabetic prescription costs in the US) and several studies suggesting its lack of efficacy in non-insulin using T2DM patients (e.g. Farmer AJ BMJ 2012;344:e486), even though currently 63.4% of T2DM use SMBG daily
  • The analysis, as with pretty much all meta-analyses, is limited by the quality of the studies included, their size, differences in methodology in general, degree of patient education, frequency of testing, and inherent biases associated with the more intensive medicalization in those doing SMBG
  • The decrease in A1C of -0.33% is often not considered to be clinically significant (typically defined as a change of 0.5%)
  • So, this study does suggest efficacy of SMBG monitoring, albeit perhaps of marginal clinical significance. As an intervention, it does medicalize patients much more than just taking a pill. And this has the potential for both positive and negative effects: the positive side is that it may empower patients in involving them more in taking ownership and treating their condition, and for some patients, this involvement might be important in helping them deal psychologically with a potentially devastating disease; the negative side is that for some patients it might create lots of anxiety and perhaps over-focus/dwelling on their medical problems and perhaps reinforce a more passive, “sickness” mentality which could decrease their ability to function.
  • This last difference exposes one of the contradictions of RCTs: they look at a large group of individuals, with some exclusions, but cannot really replicate the actual patient one is treating. It may well be that some patients who want to control their bodies and illnesses more, actually do much better with SMBG than decreasing their A1C by the 0.33% as above, perhaps using the daily blood sugar feedback as a motivation for more lifestyle changes (and, even if the A1C does not plummet, these lifestyle changes might have much broader healthful consequences). Others who may become more anxious or are not interested in this level of involvement, may get no benefit, or the experience might actually be negative. And the sum of these patients in the larger RCTs may then reveal only a mediocre outcome, obscuring the potential benefit for perhaps a lot of people. The real trick might be to figure out who is motivated by the SMBG and use this tool to help them with their diabetes management. And perhaps not using or stopping SMBG in those who do not really benefit. So, yet again, one size just does not fit all….

Primary Care Corner with Geoffrey Modest MD: E-Cigarettes Help Smoking Cessation??

24 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There has been a lot of controversy about the potential benefits of using e-cigarettes to help current smokers quit vs the potential harms of e-cigs in normalizing and promoting nicotine use for nonsmokers, possibly leading to smoking the much more toxic regular cigarettes. A recent large data analysis from the UK did suggest that e-cigs may be a helpful aid for smoking cessation (see doi.org/10.1136/bmj.i4645).

Details:

  • England has a “liberal regulatory framework for e-cigarettes and has seen a considerable growth in their use”
  • This study looked a 2 sources of information over time: the Smoking Toolkit Study (monthly household, face-to-face scripted surveys of a representative UK population >16 yo, with data from 2006 on 170,490 individuals, of whom 41K were past smokers, 38K were current smokers, with about 1200 smokers being surveyed quarterly); and statistics on the use of the  English National Health Service (NHS) stop smoking services (8,029,012 people had set quit dates)

Results:

  • The prevalence of self-reported quit attempts decreased over time (45.4% in 2006 to 31.2% in 2014), but the percent of successful quit rate rose from 10.6% to 15.2%
  • There as a striking increased use of e-cigs, beginning in 2012 and increasing to 35% by 2014
  • E-cig use by smokers was positively associated with successful attempts to quit, by 0.098% [0.064 to 0.132); P<0.001] for every 1% increase in the prevalence of e-cigarette use by smokers
  • E-cig use in quit attempts was also positively associated with quit success, by058% [0.038 to 0.078; P<0.001] for every 1% increase in e-cigarette use during a recent quit attempt
  • Data were inconclusive about the association between current e-cigarette use and the overall rate of quit attempts, use of NRT (nicotine replacement therapy) bought over the counter, use of prescription treatment, or use of behavioral support. [Note: “inconclusive” does not mean “ineffective”]
  • There was evidence that expenditure on mass media was positively associated with use of stop smoking services
  • A negative association was found between e-cigarette use during a recent quit attempt and use of NRT obtained through prescription by 0.098% for every 1% increase in e-cig use in a quit attempt (P=0.04), and there was a pretty remarkable but apparently nonsignificant decrease in over-the-counter (OTC) NRT purchases from 40.0% to 20.6% of smokers [e., it appeared that the more e-cigs were used, the less NRT used. Substitution by the patients??)

Commentary:

  • The above numbers were adjusted for changes in differences in stop smoking services over time, introduction of a smoking ban in 2007, change in minimum age of sale of cigarettes from 16 to 18 yo in 2007, and changes in price of cigarettes
  • The overall decrease in smoking prevalence in England dropped 1 percentage point between 2014-5.
  • From their mathematical modeling: in 2015, quit attempts was 32.5% (of 8 million smokers) and the prevalence of e-cig use in quit attempts was 36%, so 54,288 more quitters stopped at least short to medium term. And if 2/3 relapse (the usual %), then e-cigs would have contributed to 18,000 additional long-term quitters.
  • And, a 40yo who quits smoking is likely to gain about 9 years of life
  • The generalizability to other areas may be limited by their differences to UK policies on e-cigs as well as smoking cessation supports, media campaigns, etc
  • Other studies do find a rise in e-cig experimentation in nonsmokers, though the rate of regular use is <1%
  • As mentioned in prior blogs (e.g., see http://blogs.bmj.com/ebm/2016/05/10/primary-care-corner-with-geoffrey-modest-md-e-cigarettes-as-a-tool-to-quitting-smokingharm-reduction/ ), I have had some impressive success with e-cigs (either initiated by the patient or by me) in getting some really long-term smokers to quit. I do regularly try the other motivational and medical therapies first, so the group who do finally quit with e-cigs is a pretty resistant one. So, my bottom line is that if e-cigs are legal and available, I do consider it part of my smoking cessation options, even as a means for harm reduction (i.e., using e-cigs to decrease cigarettes, which have 3000 additives and some known to be carcinogenic). And I do counsel adolescents in particular about the potential harm of initiating e-cig use and nicotine’s profound addiction potential.

Primary Care Corner with Geoffrey Modest MD: Lower Blood Pressure in Elderly and Decreased Morbidity

20 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent study of older community-dwelling high-risk hypertensive patients looked at the relationship between their achieved blood pressure and cardiovascular outcomes (see Myers MG Hypertension. 2016;68:866).

Details:

  • 6183 community-dwelling Ontario residents >65yo on antihypertensive therapy, followed mean of 4.6 years (the CHAP study: Cardiovascular Health Awareness Program)
  • Blood pressure measured (as in the SPRINT trial) by AOBP (electronic automated office blood pressure). In Ontario, the protocol was that the person rest seated in a quiet place, undisturbed before and during the readings. The research staff did not speak to the subjects or interact with them. The patient did not wait 5 minutes, but the AOBP recorded the blood pressure each minute for 5 minutes and computed the mean value. The AOBP was recorded in community pharmacies, which a different study found to be similar to AOBP done in the office of the patient’s own family physician. In the SPRINT trial, the initial reading was after the patient seated and wait 5 minutes in quiet, then the blood pressure was measured using a similar automated machine as in the Ontario study
  • Mean age 76, 42% male, 6% self-reported smokers, 48% self-reported high blood cholesterol, 27% diabetic, 12% congestive heart failure
  • Mean AOBP: 134.3/72.9 mmHg. Mean number of antihypertensive meds = 1.8-1.9 for each 10mm blood pressure category

Results:

  • 904 nonfatal and fatal cardiovascular events during the follow-up period
  • Multivariate adjustment (adjusting for age, sex, coronary artery disease, cerebrovascular disease, congestive heart failure, diabetes, number of anti-hypertensive meds, hypercholesterolemia, smoking, self-reported health status, BMI, number of unique drugs) found that, as compared to an achieved systolic of 110-119 mmHg [n=837]:
    • <110 mmHg: HR 1.38 (1.04-1.81) [n=546]
    • 120-129mmHg: HR 1.30 (1.01-1.66)[n=1308]
    • 130-139mmHg: HR 1.23 (0.96-1.58), nonsignificant [n=1259]
    • 140-149mmHg: HR 1.18 (0.90-1.54), nonsignificant [n=984]
    • 150-159mmHg: HR 1.43 (1.08-1.90) [n=604]
    • 160+ mmHg: HR 1.85 (1.42-2.41) [n=645]
  • Multivariate adjustment for achieved diastolic blood pressure, as compared to referent of 60-69 mmHg [n=1788]:
    • <60 mmHg: HR 1.31 (1.07-1.61) [n=636]
    • 70-79 mmHg: HR 1.02 (0.87-1.21), nonsignificant [n=2212]
    • 80-89 mmHg: HR 1.08 (0.88-1.32), nonsignificant [n=1133]
    • 90+ mmHg: HR 1.14 (0.86-1.52), nonsignificant  [n=414]
  • Multivariate adjustment for pulse pressure (systolic minus diastolic), with 50-59 mmHg being referent [no comment on how many people were in each group]:
    • <50 mmHg: HR 1.06 (0.87-1.29), nonsignificant
    • 60-69 mmHg: HR 1.07 (0.87-1.30), nonsignificant
    • 70-79 mmHg: HR 1.10 (0.88-1.38), nonsignificant
    • 80-89 mmHg: HR 1.33 (1.03-1.72)
    • 90+ mmHg: HR 1.83 (1.42-2.34)
  • No difference in outcome in the 1673 patients with diabetes vs the 4510 nondiabetics

Commentary:

  • So, overall, this study found increased CV outcomes in patients with achieved systolic blood pressure below 110 mmHg or if 120-129 mmHg (vs the nadir of 110-119 mmHg), and not again until >150 mmHg; an increase only with diastolics <60 mmHg; and an increase when the pulse pressure was >80 mmHg (the latter likely reflecting stiff arteries, as with diffuse atherosclerosis). By the way, this nadir of SBP 110-119 mmHg was the same as in the SPRINT trial
  • This observational study, as with many observational studies, did find a J-curve in clinical outcomes in hypertensive patients, with increased morbidity/mortality in those with both lower and higher achieved blood pressure. This was not found in the prospective randomized-controlled SPRINT or ACCORD trials, where the lower blood pressure was better, suggesting that there might be a selection bias here: i.e., are those with lower blood pressure different from the others? Do they have non-blood pressure related terminal illnesses, like cancer or infections or perhaps worse cases of diabetes or heart failure, which leads to lower blood pressure and also to higher morbidity/mortality?)
  • One thing I have commented on in the past: there is a rather strong trend in the medical literature to put many study details in a “supplement”, which i think often includes critical details. In the above study, for example, there were no data on the number of patients in each cell of achieved systolic and diastolic blood pressures, except in the supplement, and none anywhere on the pulse pressure categories. It seems to me to be very important information (was the lack of statistical significance in some groups due to small numbers of patients??). My guess is that pretty few readers go to the trouble of going online to get this information; it is much less of a hassle to just accept the authors’ interpretations in the main article. And if we just got the PDF from the author by email, the supplementary material is not included (at least in my experience). And I pretty often do find very important information buried in the supplements, in the relatively few times I scour them, and this information sometimes changes my interpretation of the article.
  • One of my biggest concerns with clinical management of hypertension is that in the typical rushed clinical environment, most of us simply accept the automated blood pressure readings of the medical assistants as being accurate. This brings up several very important issues in probably what is the most common clinical issue we see in adult patients and one that we can potentially positively affect:
  • The automated machine is not always accurate (e.g. in patients with atrial fibrillation or frequent dysrhythmias)
  • Typically the patient walks into the room and has the blood pressure done quickly in a not-so-restful environment (and many of my patients are pretty unfit physically/deconditioned, so have a much much higher blood pressure than when I retake a manual pressure when they are sitting quietly in the exam room)
  • I do routinely recheck blood pressures in the exam room, typically after leaving the patient sitting on the exam table for about 2 minutes, often with the lights out (I go into the other room to write my note), and find in this not-very-scientific study that about 50% of the medical assistant blood pressures are really pretty close to what I get, 40+% are much lower than the medical assistant pressures (and often by 20-40 mmHg!!!), and the rest are much higher than the medical assistant values (not sure why, but i sometimes get manual pressures of 190/108, when the medical assistants get 118/77…..)
  • There is a significant literature suggesting that clinical outcomes track much better with 24-hour ambulatory blood pressure monitoring (ABPM) or home-based blood pressure (I do ask patients to bring in their cuff and make sure it compares well with the manual recording I get, done at the same time). See the URLs below for more articles on this. and the USPSTF does now (finally) endorse non-clinic based blood pressures (see below)
  • Using AOBP in this Ontario study, similar to the SPRINT study, is an interesting hybrid, which sounds pretty good to me, though i have not seen much in the literature on this. But again, to apply these trials to clinical practice, we need to get blood pressure readings that approximate how it was done in the studies (i.e., at least with having the patient rest in a quiet room for awhile, or using ABPM; though with ABPM, there is only one cutpoint: either above or below 135/85, not with the fine gradations of the SPRINT or other trials assessing treating blood pressure to different targets.
  • One of the strengths of this study is that it was not a formal study with selected patients according to specific inclusion and exclusion criteria, but more of a community approach, likely more reflective of our actual clinical practice (i.e., there is decreased internal validity in that there may have been very uneven distribution of patients in the different categories of achieved blood pressure, perhaps with healthier patients overall able to achieve an SBP in the 110-119 range, or their clinicians were more aggressive in trying to lower their blood pressure; yet more external validity in that it more closely reflects real-world clinical practice. one drawback to the study was that AOBP was measured only one point in time. and they did not have much granular data, such as how long the patient had hypertension or what time of day the AOBP was recorded, or how bad the heart failure was, etc. But it was intriguing that the results (best to have SBP 110-119) was so similar to that of the rigorous SPRINT trial.

See http://blogs.bmj.com/ebm/category/hypertension/ for an array of articles/reviews on hypertension, including a recent one showing that blood pressure variability is associated with more cardiovascular disease

See http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/ for a brief review of ambulatory BP monitoring and the USPSTF recommendations

See http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/ for the overall SPRINT trial

See http://blogs.bmj.com/ebm/2016/06/02/primary-care-corner-with-geoffrey-modest-md-sprint-trial-elderly-subgroup-study-of-lower-blood-pressure-goal/ for an analysis of the elderly subgroup of the SPRINT trial, finding improvement in cardiac outcomes in those >75 yo with achieved SBP of 123

See http://blogs.bmj.com/ebm/2016/05/03/primary-care-corner-with-geoffrey-modest-md-home-blood-pressure-monitoring/ for some of the data on home blood pressure monitoring

See http://blogs.bmj.com/ebm/2015/10/13/primary-care-corner-with-geoffrey-modest-md-bp-self-monitoringself-titrating-decreases-bp/ shows the benefits of patient self-monitoring blood pressure and self-titrating meds

Primary Care Corner by Geoffrey Modest MD: pap in women with HPV vaccine jnci2016

19 Oct, 16 | by EBM

By Dr. Geoffrey Modest

Given the recent 2 articles on cervical cancer screening (http://blogs.bmj.com/ebm/2016/10/12/primary-care-corner-with-geoffrey-modest-md-cervical-cancer-screening-less-frequently/ and http://blogs.bmj.com/ebm/2016/10/17/primary-care-corner-with-geoffrey-modest-md-cervical-screening-guidelines-from-asco/), I thought I would add (briefly) a third to the troika (see doi: 10.1093/jnci/djw216). Funded by National Cancer Institute of the NIH and done by Harvard School of Public Health.

Details:

  • This is a mathematical modeling of the cost-effectiveness of different cervical cancer screening approaches in HPV-vaccinated women
  • They looked at different levels of cost-effectiveness thresholds: from $50K to $200K per quality-adjusted life-year (QALY) gained

Results:

  • In women who were fully vaccinated with either the bivalent or quadrivalent HPV vaccine, optimal screening strategies involved either cytology or HPV screening alone every 5 years starting at age 25 or 30 (cost-effectiveness ratios ranging from $34,680 to $138,560 per QALY gained
  • In women vaccinated with the nonavalent vaccine (that being: 9 HPV genotypes), only HPV testing by itself was efficient, with both decreased frequency (every 10 years) and starting later at age 35 ($40,210 per QALY) or age 30 ($127,010 per QALY)
  • If there were in reality decreased nonavalent vaccine efficacy, then the 10-year HPV screening should start at age 25 or 30.

Commentary:

  • This article does highlight the issue mentioned briefly in the prior 2 blogs: HPV vaccination might significantly change the cervical cancer screening algorithm
  • The nonavalent vaccine, the one we use now, covers 90% of the carcinogenic HPV types (including the biggies 16/18), as well as 2 of them (6/11) associated with noncarcinogenic genital warts
  • But, there are certainly concerns about directly applying the above:
    • The US rates of HPV vaccination remain <50%
    • There are very limited real-world data on the effectiveness of the vaccines in reducing HPV infection and, especially, the development of precancerous or cancerous lesions
    • This relies on mathematical modeling, which without any real data, is likely fraught with potential errors in assumptions
    • There is potential collateral benefit from screening less: fewer harms from unnecessary colposcopies (???though are we missing some of the “necessary” ones??)
  • So, this adds some to the argument that we need to screen less. The analysis/conclusions would be different if women did not receive the vaccine before they had sexual relations (though, important to remember that HPV can be transmitted without penetrative sexual relations), or did not receive the full series of shots. And the real issue is waiting for real data about the effects of vaccinations in the real world on the incidence of actual CIN and advanced cervical cancer and morbidity/mortality. I am also a little leery about the effect of doing many fewer pelvic exams: I find now that some newer clinicians are less confident doing them, and sometimes do not do them when there are clear clinical indications. This potential adverse effect should somehow be factored into the risk/benefit analysis…

Primary Care Corner with Geoffrey Modest MD: Orthostatic Hypotension and Increased Heart Failure and Mortality

19 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There was an interesting subgroup analysis of the ACCORD blood pressure wing (Action to Control Cardiovascular Risk in Diabetes) which found that those with orthostatic hypotension (OH) had a significantly higher risk of mortality and heart failure events (see Fleg JL, Hypertension. 2016;68:888 ). Details:

  • The ACCORD trial had 10,251 high-risk patients with type 2 diabetes, hemoglobin A1c >7.5%, and were between 40 and 79 years old with cardiovascular disease or 55 to 79 years with anatomic evidence of subclinical atherosclerosis, albuminurea, LVH, or >= 2 additional cardiovascular risk factors. 4733 were randomly assigned to intensive vs standard blood pressure control in a non-blinded trial, with target systolic blood pressure (SBP) of <120 vs <140 mm Hg, and with no requirements as to what medications to give (clinicians’ decisions)
  • 4266 participants were involved in this analysis, with blood pressure measured at baseline, and at the 12 month, and 48 month follow-up visits. The blood pressure was measured using an automated oscillometric device after the patient had been seated at least five minutes, with the blood pressure determined three times at one minute intervals. The patients then stood up and had their blood pressure measured every minute for three minutes. The patients were asked if they experienced dizziness or felt light-headed.
  • Orthostatic hypotension (OH) was defined as a decline in SBP > 20 mmHg or decline in DBP > 10 mmHg
  • The average difference in blood pressure achieved between the intensive vs standard groups was 14.2/6.1 mmHg, with the mean number of medications being 3.4 for the intensive group and 2.1 for the standard group.
  • Serious adverse events related to the intervention, including hypotension and syncope, were found in 3.3% of the intensive group compared to 1.3% of the standard group, with p<0.001

Results:

  • OH occurred at least once in 852 people (20.0%). In the adjusted model, this occurred most commonly in women, current smokers, those with higher baseline SBP, higher A1c, and those on beta blockers, alpha blockers or insulin. Of note, neither age nor assignment to intensive vs. standard BP treatment goals was associated with OH
  • Approximate 5% of all patients, independent of group, felt dizzy on standing. The incidence was slightly more in the intensive group but only at the 48 month examination.
  • There was no significant difference in OH prevalence, incidence, or resolution between those in the intensive vs. control groups.
  • People with OH were about twice as likely to report symptoms of dizziness on standing than those without OH, but this was only in about 17-20% of the patients who were symptomatic.
  • Those with OH had an 85% higher risk for heart failure deaths or hospitalizations (p= 0.01) and 62% higher risk for total mortality (p= 0.02).

Commentary:

  • In my experience, beta blockers are the medication most commonly associated with OH and large decreases in blood pressure on standing, even in those with high sitting pressures.
  • It is not so surprising that those with higher A1c’s and on insulin have more OH, since they may well have more autonomic neuropathy, and there may also be some direct insulin-induced vasodilation, perhaps through endothelium-dependent mechanisms.
  • Or that smokers have more OH (probably more atherosclerotic disease of their large arteries, leading to higher SBP but lower DBP because of their nondistensibility)
  • Or in those who had initially higher SBP (again perhaps related to more atherosclerotic large vessel disease, leading to more isolated systolic hypertension)
  • It is, however, unexpected and striking that they found no correlation of OH with age. All of the studies I have seen have shown a significant increase with age. Perhaps part of the reason is that in this study they had an 80-year-old cut off.
  • And, there was no association with whether the patient was in the more aggressive blood pressure lowering group or not (which also supports checking orthostatics in patients with higher blood pressures)
  • So, in this study, it was unclear whether OH was simply a marker of people at higher risk of morbidity/mortality (e.g. more advanced diabetes, with more autonomic neuropathy, etc. as above), or whether it was the cause. but given the not-so-unlikely possibility of the latter being part of the issue, I think it makes sense to assess OH regularly in patients (and i do so in all elderly hypertensive patients, even if they do not have diabetes, and have found, i think, pretty impressive 30+ mmHg drops in blood pressure even in those with systolics in the 150-160 range, and not so uncommonly…) and customize therapy to avoid excessive falls in blood pressure, whether they are symptomatic or not (the reason being: even if asymptomatic, perhaps there are times when they eat/drink less at home or outside in the heat and they become symptomatic, fall, etc; and perhaps the low flow associated with OH really is not so good for the brain, heart, kidneys, etc in the longterm.)
  • For example, there are some studies showing cognitive decline with low blood pressure: see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/).
  • Another important point from the study was that dizziness is not commonly reported with clear-cut OH by blood pressure measurement (i.e. we should not rely on reported dizziness as a reliable marker of OH), and that OH is not a consistent finding each time it is measured.
  • All of this supports my prior suggestions that we measure orthostatic blood pressures in older patients on a regular basis, even if the SBP is in the 150 range, and adjust meds accordingly (?ACCORDingly).

 

(See http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/ for more studies on orthostatic hypotension, including the finding that initial hypotension on standing is in fact much more common than standard orthostatic hypotension after a couple minutes)

Primary Care Corner with Geoffrey Modest MD: H pylori regimens, stratified by clarithromycin sensitivity

18 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent systematic review and network meta-analysis of treatments of H Pylori infections in countries with high vs low clarithromycin resistance (see doi:10.1136/gutjnl-2016-311868). A network meta-analysis is helpful when there are not head-to-head comparisons of all of the therapies, using mathematical assumptions/manipulations to approximate results across studies in an attempt to approximate the likely results if there were such direct comparisons.  There was another recent blog which did a similar analysis of H pylori treatments but was not stratified by clarithromycin sensitivity (see http://blogs.bmj.com/ebm/2015/09/03/primary-care-corner-with-geoffrey-modest-md-h-pylori-regimens/ from the BMJ in 2015).

Details of the current analysis:

  • 117 trials with 32,852 patients analyzing 17 H pylori eradication regimens were included
  • Mean age 48, trials ranged from 58 to 1463 patients, with mean of 281
  • All had documented H pylori infections by urea breath test, histologic or bacterial culture exams, or stool antigen
  • All had documentation of H pylori eradication by intention-to-treat analysis, at least 4 weeks after therapy
  • The authors analyzed results of treatment stratified by clarithromycin resistance, ascertained by a literature review of it prevalence by the countries where the RCTs were done, with a cutpoint of 15% resistance rate.

Results:

  • Compared to a 7-day course of clarithromycin-based triple therapy:
    • Overall: best was 14 days of sequential therapy, OR= 3.74 (2.37-5.96)
    • In areas of high clarithromycin-resistance: best was 14 days of sequential therapy, OR= 6.53 (3.23-13.63). and this did not diminish in the more recent studies where resistance was likely to increase; second best was bismuth, PPI and 2 of amoxacillin/tetracylcine/metronidazone/clarithromycin for 10 or 14 days, with OR 3.6
    • In areas of low clarithromycin-resistance: best was 10 or more days of hybrid therapy, OR= 2.85 (1.58-5.37); second best was continuous therapy (e.g. PPI, amoxacillin and clarithromycin) at least 10 days
    • The lowest efficacy overall was triple therapy with metronidazole for 7 days
    • Overall, better efficacy with longer treatments, which mostly meant 14 days
    • Severe adverse events were rare in all regimens, though happened more often in the longer courses of therapy

Commentary:

  • H pylori infection is unbelievably common, in >50% of world’s population, and is associated with peptic ulcer disease, active gastroduodenal ulcer bleeding, gastric MALT (mucosa-associated lymphoid tissue lymphoma) and >75% of gastric cancers
  • H pylori eradication is recommended in patients on long-term NSAIDs, anti-platelet agents/low-dose ASA, and those with unexplained iron-deficiency anemia or ITP, per the Maastrich IV/Florence Consensus Report in 2012 (see Gut. 2012; 61:646) [as mentioned in prior blogs, see URL at the end of this blog, i saw a dramatic case 20 years ago of a person with intractable steroid-resistant ITP, scheduled for surgery, but the Lancet had a small case report showing benefit of H pylori treatment. so I tested and treated him for H pylori and the ITP melted away, off all meds, within weeks. and without surgery
  • The standard therapy has been a PPI, amoxacillin and clarithromycin or metronidazole, but the effectiveness has been waning.
  • There are some concerns about generalizing the results of the study above. For example all of the 14 day sequential therapy trials were done in Asia. and the inherent and different biases in the different studies, as well as patient characteristics across studies, make confident conclusions difficult (e.g. some studies did not even record smoking prevalence), and studies had different levels of blinding
  • Countries with high clarithroresistance: China, Croatia, France, Greece, Hong Kong, India, Iran, Italy, Japan, Morocco, Spain, Saudi Arabia, Singapore, Turkey
  • Countries with low clarithroresistance: Chile, Ecuador, Finland, Kenya, Korea, Kuwait, Mexico, Taiwan, Thailand, UK, US, Kosovo, Palestine, Romania (last 3 with no recorded resistance rate)
  • Unfortunately, and a bit surprisingly, it was really hard to find out exactly what the therapies were (they were all combined into categories, such a “sequential” or “hybrid” therapies), even after scouring this article and its supplement. My best guess is the following:
    • Sequential therapy for 10 days: first 5 days using PPI (g.omeprazole 20mg) and amoxacillin 1gm; followed by PPI, clarithromycin 500mg and metronidazole 500mg for the remaining 5 days (some studies have substituted tinidazole 500mg for the metronidazole 500mg). all meds given BID
    • Hybrid therapy for 14 days: first 7 days PPI (g.omeprazole 20mg) and amoxacillin 1gm; followed by PPI, amoxacillin 1gm, clarithromycin 500mg and metronidazole 500mg for 7 days (again, some studies substituting tinidazole 500mg for metronidazole 500mg). all meds given BID
    • So, the hybrid therapy seems to be the same as the sequential therapy, with amoxacillinfor the whole course instead of just the first half
  • The sequential therapy (which includes clarithromycin at the end) works even with clarithromycin resistance, with 89% of clarithromycin-resistant strains responding vs 29% with standard therapy — the posited mechanism for resistance being that H pylori had developed efflux channels for clarithro that rapidly remove the drug from the bacteria and that amoxacillin changes the structure of the cell membrane to prevent effective clarithromycin efflux and therefore resistance. (see Ann Intern Med 2007; 146:555-563, and http://blogs.bmj.com/ebm/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-sequential-or-standard-rx-for-h-pylori/)
  • From 9/9/15 blog (see http://blogs.bmj.com/ebm/2015/09/03/primary-care-corner-with-geoffrey-modest-md-h-pylori-regimens/): “and, one very important issue in the US is that we do not have data (at least in Boston) on H pylori sensitivities. Maybe that makes sense. One of our greatest assets in Boston is the wonderful ethnic diversity here. One of the problems (at least as H pylori is concerned) is that H pylori organisms from different parts of the world are here with their different antibiotic sensitivities. So applying averaged sensitivities may not really benefit the individual patient in front of you.”
  • I personally have been using only the 10-day sequential therapy, since it was shown years ago to be superior, though there are some differences in different studies. This therapy is certainly a bit more complicated: I usually have the patient bring back the bottles of pills and either I or a nurse review the regimen in detail. In the very few cases of persistent H pylori infection post-therapy that I have seen (mostly detected by stool antigen testing), I use the bismuth-based regimen: high dose PPI bid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate240mg bid for 14 days. So far, so good.
  • But, based on the current study, I will change to the 14-day sequential therapy course. I am certainly concerned that many of my patients are getting too many antibiotics, esp azithromycin (g., see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/) and metronidazole, which are likely to breed resistance in untreated H pylori infections. So, I follow symptoms closely post-therapy, check H pylori antigen when the patient is symptomatic, and retreat with one of the rescue regimens.  If this resistance happens more often, I will switch to the hybrid regimen above.  Also, tinidazole may be more effective than metronidazole, and tinidazole is available in the US but mostly with the disincentive of a Prior Approval……. [Though, the tinidazole may be more effective in the US precisely because we use much much more metronidazole]

 Also so see http://blogs.bmj.com/ebm/category/gi-h-pylori/ has a series of blogs on H Pylori infection, including some suggesting eradication leads to lower incidence of gastric cancer, increased bleeding if H Pylori positive and taking NSAIDs (and some studies showing that eliminating H Pylori leads to lower risk of NSAID-associated bleeding), and a review of several studies of different medication regimens.

Primary Care Corner with Geoffrey Modest MD: Another Concerning LTBI IGRA Article

17 Oct, 16 | by EBM

By Dr. Geoffrey Modest

Given the recent article of the USPSTF LTBI (latent TB infection) recommendations (http://blogs.bmj.com/ebm/2016/10/11/primary-care-corner-with-geoffrey-modest-md-uspstf-ltbi-screening-recommendations/ ) I decided to bring up another study which questions the role of  IGRAs (interferon-γ release assays) –see  King TC. Am J Respir Care 2015; 192(3): 367. I initially decided that the prior articles and blogs were pretty concerning about the stability of IGRAs, but this study does add another wrinkle: it was an industry-sponsored study, still had pretty striking conclusions that 1 in 5 people with positive IGRAs would revert to negative, yet then concluded that T-SPOT.TB (one of the IGRAs) is “an accurate and reliable way to screen healthcare workers”.

Details:

  • 20,095 pairs of T-SPOT.TBresults from 16,412 health care workers (HCWs) at 19 geographically diverse US hospitals (urban, suburban, rural), looking at serial T-SPOT.TB  testing, from 2010 to 2014, where the second test result was at least 150 days after the first one.
  • 77% female, median age 41 and no other demographics included
  • Their analysis excluded those with borderline tests from either the initial or subsequent test, approx 2.3% of the results
  • Conversion was defined as a negative result turning positive; reversion was the opposite

Results:

  • The mean conversion rate was 0.8%, but 2.3% in hospitals that checked only high risk HCWs, and 0.6% in hospitals that checked all HCWs
  • The mean reversion rate was 17.6%, but 13.9% in hospitals that checked only high risk HCWs, and 20.7% in those that checked all HCWs
  • The baseline test positivity rate was 2.3%, but varied from 0-27.4%; and was 8.4% in hospitals that checked only high risk
  • There was a strong correlation between observed conversion rates by T-SPOT and reported TB incidence of the state where the hospital was located
  • 23% of those with borderline results were positive on retesting

Commentary:

  • Of course, one of the primary issues with LTBI screening is that there is no gold standard.
  • This article does cite 5 studies which challenge the IGRA’s stability and reliability.
  • The researchers think their test was better (again, remember that this is an industry-sponsored study), and had lower reversion rates than other studies because: they had higher and more rigorous cutpoints than prior T-SPOT tests (though, without a gold standard, hard really to know the effect of this on the sensitivity of the test), they have lower likelihood of sample processing errors than QuantiFERON IGRAs, but they do note that all IGRAs, which measure an immune response to TB, are subject to “biological variability”. It is also unknown in this study whether the patients had been treated or not, which other studies have suggested might be part of the reason for reversions (though the authors did not comment on this).
  • One really interesting note is that this industry-sponsored study was able to state on the one hand that though >20% of the HCWs who had a positive IGRA actually reverted to negative about 1 year later, on the other hand they concluded that the IGRA is an accurate/reliable test. It seem to me as a casual observer that the possibility of 20% false positives, which they acknowledge as a possibility, is a tad high. And any positive can lead to unnecessary but potentially toxic drugs, potential stigma, etc. So, as mentioned in prior blogs, I am sticking with the PPD, except in unusual circumstances (e.g., the patient really cannot get the PPD read in 48-72 hours).

 

Primary Care Corner with Geoffrey Modest MD: Cervical Screening Guidelines From ASCO

17 Oct, 16 | by EBM

By Dr. Geoffrey Modest

The American Society of Clinical Oncology just published guidelines for the secondary prevention of cervical cancer (see doi: 10.1200/JGO.2016.006577, or go to  http://ascopubs.org/doi/abs/10.1200/JGO.2016.006577 ). These guidelines were unusual in that they stratified the screening approach based on the country’s resources, reflecting a global initiative, and also had several differences from the current US guidelines.

Details:

  • HPV testing is recommended in all resource settings, though visual inspection with acetic acid may be used in countries with basic resources.
  • Frequency of testing:
    • For countries with maximal resources: should be from age 25 to 65, every five years if negative.
    • For countries with enhanced resources: age 30 to 65. If two consecutive negative tests at five-year intervals, then every 10 years. Stop at age 65 if consistently negative results for the past 15 years
    • For countries with limited resources: age 30 to 49 every 10 years
    • For countries with basic resources: age 30 to 49, 1 to 3 times per lifetime
  • Treatment options for patients with a positive screen:
    • In countries with more than basic resources: colposcopy, then loop electrosurgical excision (LEEP) if positive
    • For countries with basic resources: treat with cryotherapy or loop electrosurgical excision
  • Follow-up post-treatment:
    • 12 month follow-up is recommended in all settings
  • For HIV-positive women (also applies to women who are immunosuppressed for any reason):
    • Overall, screen with HPV testing twice as many times per lifetime as in the general population (as above). Screening should begin as soon as they get the HIV diagnosis [? when to start if they are born with the infection/or get it from a transfusion at age 8???].
      • In countries with maximal  resources: screen with HPV every 2-3 years
      • In countries with enhanced resources: screen with HPV at 2-3 year intervals; but if negative, every 5 years (approx 8 screenings in lifetime)
      • In countries with limited resources: twice as often as in general population (4-6 screenings per lifetime)
      • In countries with basic resources: begin screening with HPV if available, or with visual inspection with acetic acid, at age 25, then every 3 years if negative initially. [A bit unclear, since they then suggest it will be approximately twice per lifetime]. These recommendations are based on murky data…
    • Postpartum screening: overall no screening recommended during the pregnancy, partly because the normal immune changes in pregnancy can have increased HPV changes which subside after pregnancy.
      • Screen at six months in all countries other than those with only basic resources, where screen at 6 weeks since longer interval could lead to loss of follow-up [though this might apply to other countries, or areas in other countries as well…..]
    • No screening should be done in people who had a total hysterectomy for benign causes [though see blog http://blogs.bmj.com/ebm/2016/07/18/primary-care-corner-with-geoffrey-modest-md-pap-smears-post-hysterectomy-in-hiv-positive-women/, which would support general screenings in HIV-positive women who had hysterectomy]
    • And, in countries with basic resources without mass screening — infrastructure for HPV testing, diagnosis and treatment should be developed
    • Self-screening: there is evidence that women doing their own HPV sampling may improve screening coverage, though the pooled sensitivity and specificity are lower, especially for CIN2+. So, overall not suggested except in women who might otherwise not get tested at all [and the sensitivity and specificity are actually only a little lower].
    • Postulated effect of HPV vaccine: likely to decrease the incidence of HPV 16/18 cancers, and with approx 5 year later onset of disease as a result of decreasing these most-carcinogenic genotypes, so potentially can start screening later in life, and decrease screening to ages 30, 45, 60. Maybe no need to screen at all??? Or only once??  But all recommendations are pending actual data….

Commentary:

  • High-quality screening programs can lower the incidence of cervical cancer by up to 80%
  • HPV is the most frequent sexually-transmitted infection, with one study finding 43% of college women getting infected over 36 months (see Ho GYF. New Engl J Med 1998; 338:423)
  • As a point of reference, the US screening guidelines at this point are quite different from the above ASCO ones for countries with maximal resources (e.g. the USPSTF recommendations):
    • Begin at age 21, do cytology screening only until age 30, and then every 3 years if normal. HPV testing not recommended because of higher likelihood of unnecessary follow-up and procedures (HPV infection tends to be transient)
    • After age 30, either continue cytology only every 3 years, or do cytology/HPV co-testing every 5 years, if normal results
    • Stop at age 65 unless there is increased risk (history of abnormal screens, prior HPV-related disease, immunocompromise, DES exposure); and if there are 2 negative consecutive co-tests or 3 negative cytologies within prior 10 years; and no history of high-grade dysplasia or worse
  • Although ASCO cites the importance of HPV testing, they do not make formal recommendations about primary HPV testing vs co-testing, noting just that some countries and regions have moved towards adopting primary HPV testing (see http://blogs.bmj.com/ebm/2016/10/12/primary-care-corner-with-geoffrey-modest-md-cervical-cancer-screening-less-frequently/ )
  • The American College of Obstetricians and Gynecologists also just came out with their recommendations in 2016 (though, not sure what to make of this: but these guidelines were retracted from the January 2016 issue of their publication Obstetrics and Gynecology, and I could find only recommendations for HIV-positive women, though these were also retracted), with a few differences from ASCO. for HIV infected women:
    • Start screening within one year of onset of sexual activity, but no later than age 21
    • Screening should be continued throughout a woman’s lifetime and not stop at age 65
    • For women less than 30 years old:
      • Cytology screening (without HPV testing) should be repeated in 12 months (though some people feel it should be followed in six months)
      • If three consecutive cervical cytology tests and normal, follow-up cervical cytology should be done every three years
      • If ASCUS on cytology, and reflex HPV testing is positive, then colposcopy. If HPV testing results are not available, repeat cytology in 6 to 12 months if more advanced dysplasia is found, refer for colposcopy
    • For women older than 30 years old, do cervical cytology or co-testing:
      • If only cytology is done, follow-up is as for women less than 30 years old
      • If co-testing is done and negative, repeat at three years; if cytology is negative and HPV positive, repeat in one year (though if HPV 16/18 is present go directly to colposcopy). if either of the co-tests at one year is abnormal, colposcopy
    • The hope is that as HPV vaccination becomes more widespread, the incidence of cervical cancer will decrease significantly as well as the need to screen for it; though this is in the relatively distant future, given the high prevalence of HPV infections currently, and the vaccine does not help those currently infected or with abnormal cytology from infection
    • They do recommend starting screening at age 25, as is done in several countries in Europe for example, noting that there is lack of evidence of the benefit of decreased cancer risk in those under 25 (very uncommon), and potential harm or screening and overtreatment. The United States still recommends initiation of screening at age 21. And though HPV infections are remarkably common in women under 25 (as noted in study above), HPV infections clear spontaneously, and 90 to 95% of those with even LGSIL as well as many with high-grade lesions regress spontaneously
    • And they recommend HPV screening at age 25 in countries with maximal resources, different from the general recommendations in the US to start HPV screening at age 30
    • So, my guess is that the formal US recommendations will change significantly in their next iteration (the USPSTF recommendations date from 2012, with an anticipated update 2018). Perhaps internal controversy led to ACOG retracting their guidelines??  But it is pretty clear that recently the approach to cervical cancer screening has changed significantly in other countries.

Primary Care Corner with Geoffrey Modest MD: Colchicine May Lower Cardiac Risk in Patients with Gout

14 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There have been several articles suggesting that allopurinol is associated with decreased cardiovascular events (for example, see http://blogs.bmj.com/ebm/2016/04/04/hyperuricemia-allopurinol-decreases-cardiac-events/ ). This might be attributed to the cardiotoxic effects of hyperuricemia itself, or perhaps through its association with the metabolic syndrome (see the above allopurinol blog for more details, as well as http://blogs.bmj.com/ebm/2015/11/03/primary-care-corner-with-geoffrey-modest-md-uric-acid-lowering-cardiovasc-benefit-and-an-evolutionary-perspective/ for an evolutionary perspective).  However a recent study found that colchicine in patients with gout also seems to be associated with fewer cardiovascular events (see Solomon DH. Ann Rheum Dis 2015; doi: 10.1136/annrheumdis-2015-207984).

Details:

  • All patients were identified with a diagnosis of gout in their electronic record in a large academic hospital (99% accurate diagnosis, on a sample of 100 records) and linked them with cardiovascular outcome data and medication claims from Medicare.
  • 501 colchicine users (defined as those with colchicine prescribed, but no previous colchicine prescriptions in the past 90 days) and 501 nonusers. Mean follow-up 16.5 months
  • Mean age 73, 36% female, 72% white/18% black/4% Hispanic, 13% known CV disease, 10% prior heart failure, 38% diabetes, 40% on aspirin, 38% never smokers, BMI 30, 42% chronic kidney disease.
  • Primary outcome: MI, stroke, or TIA.
  • However, there were some significant differences between colchicine users and nonusers, including: hypertension in 77% of colchicine users and 28% of nonusers, statin use 50% vs. 16%, uric acid levels 8.4 mg/DL vs. 7.1 (but of note, only 278 of the 1002 patients actually had uric acid levels documented), 42% vs. 16% were on allopurinol, 42% vs. 9% were on NSAIDs, and 42% vs. 12% were on oral steroids.

Results:

  • 28 primary CV events were observed among colchicine users and 82 among nonusers, incidence rates per 1000 person-years were: 35.6 for users and 81.8 for nonusers.
  • With full adjustment (age, gender, race, history of CV disease and risk factors, as well as medications including NSAIDs, allopurinol, chronic kidney disease), colchicine was associated with:
    • 49% lower risk of all primary CV outcomes, HR 0.51 (0.30 – 0.88)
    • 73% reduction in all-cause mortality, HR 0.27 (0.17 – 0.43)
  • The curves for all of these outcomes were tending to splay apart over time. Of note, however, those who were on colchicine for the longest did have more cardiovascular events, with the group doing best being those who used colchicine less than three months.
  • Though only a quarter of the patients had uric acid levels checked, there was a similar trend by uric acid levels as with the primary analysis.

Commentary:

  • The putative mechanism by which colchicine might decrease cardiovascular events is through its down regulation of inflammatory cytokines and neutrophil chemotaxis, decreasing inflammation. And it does have clinical benefit in several inflammatory conditions including recurrent pericarditis, familial Mediterranean fever, …
  • As with all observational studies, there may be inherent biases. They did try to control for underlying diseases, but there still could be some bias to not using colchicine in those who were sicker. There might also have been a bias that those on colchicine may have been more willing to take medications, which could elicit a higher placebo effect. It would be really helpful to have a controlled trial of chronic allopurinol vs. chronic colchicine use in patients with recurrent gout attacks, both to compare the efficacy in preventing gout as well as differences in cardiovascular outcomes.
  • So, how did this study affect our clinical practice? Probably not a lot, without a study showing clearly that colchicine is as effective as allopurinol/hypouricemic agents in decreasing cardiovascular events. Since there are still more data supporting the cardioprotection of hypouricemic agents, I will still continue with them primarily. However, in the remote past, I had many patients on chronic colchicine for recurrent gout with excellent effectiveness in gout attack prevention. At a dose of 0.6 mg per day (though some clinicians used 0.6 mg bid), colchicine was very well-tolerated and seemed to have fewer adverse effects than allopurinol. So, as a result of this current study, I am more inclined to use chronic colchicine again, especially if someone is intolerant of the hypouricemia (In this latter case, I had moved more to treating the recurrent gout attacks with intra-articular steroids.)

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.

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