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Archive for June, 2017

Primary Care Corner with Geoffrey Modest MD: Teens birthrate and sexual activity/contraception use

28 Jun, 17 | by gmodest

by Geoffrey Modest

2 related articles were recently published by the CDC.

1. In the United State from 1991 to 2014 the birth rate among teens age 15 to 19 hasdeclined by a dramatic 61%from 61.8 per 1000 to 24.2 per 1000, with larger % decreases in ethnic/racial minorities (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6516a1.htm?s_cid=mm6516a1_w ). However the birth rate remained approximately twice as high for Hispanic and non-Hispanic black teens compared to non-Hispanic white teens. There are also significant geographic and socioeconomic disparities. See prior blog  for the full assessment . In brief:

— from 2006 to 2014, a 41% decline in birthrate overall, to 25.4 per 1000 female teens

— Hispanic: decreasing to 39.8 per 1000, a 51% decrease from 77.4 per 1000

— Black: decreasing to 37.0 per 1000, a 44% decrease, from 61.9 per 1000

— white: decreasing to 18.0 per 1000, a 35% decrease from 26.7 per 1000

— there is large geographic variability, for example the Hispanic birthrate in 2014 varied from 17.0 per 1000 in Maine to 58.0 per 1000 in Oklahoma; Black birthrate varied from 14.0 per thousand in New Hampshire to 54.6 per thousand in Arkansas; white birthrate varied from 4.8 per 1000 in New Jersey to 39.2 per 1000 in West Virginia. And, within states, sometimes the racial disparities remain very high: eg, in Nebraska the birth rate for whites was 16.2 (approx the national average) whereas the rates for black and Hispanic (42.6 and 53.9) were far above the national average for these groups.

–and, there was a higher birth rate in those who are unemployed, have lower levels of education and lower incomes.

Commentary:

–as a perspective, the overall US birth rate in 2011 for 15-19 years old females was 34.0 per 1000, vs 13 per 1000 the same year in Canada. And the rate in France was 7 per 1000 and in Germany 5 per 1000.

so,

–very dramatic changes in teen birth rate, with a narrowing of the gap for racial/ethnic minorities as compared to whites. However, as noted, the gap remains significantly discordant.

–And, I suspect, a large part of the geographic gap reflects access to and quality of care. And there are major concerns about the future: the trump administration etc are pushing for decreased Planned Parenthood (potentially leading to even less access to care/contraception for poor and minority patients, with anticipated increases in pregnancy rates, and likely maternal and fetal death rates) and even cutbacks in maternity care. For example, another blog showed that a restrictive abortion law in Texas led to an 18.2% decline in abortions; and there have been a plethora of studies linking lack of prenatal care to poorer outcomes.

–and, the overall social environment, getting worse in the trump era, no doubt will add to the problem: lower incomes, cutbacks in social programs (including perhaps health insurance), fewer safety net programs overall, and social upheaval in general (including targeting immigrants) will predictably lead to even less access to care, less sense of hope for the future, lower self-esteem, and poorer health outcomes, including pregnancy rates.

———————————————————

2. Another CDC article evaluated sexual activity and contraceptive use among teens aged 15-19 in the US from 2011-2015 (see https://www.cdc.gov/nchs/data/nhsr/nhsr104.pdf),finding:

 

–42.4% of never-married female teens (4.0 million) and 44.2% of never-married male teens (4.4 million) had sex at least once by the time of the interview; these numbers were similar to those from 2002 and 2006-2010, though looking back to 1988 there was a decline (downward trend, with p<0.05). By ethnicity/race, from 2002 to  2011-15:

–Hispanic female: 37.4% in 2002, 41.2% in 2011-15; Hispanic male: 54.8% to 45.7%

–non-Hispanic white female: 45.1% in 2002, 44.3% in 2011-15; non-Hispanic white male: 40.8% to 42.8%

–non-Hispanic black female: 56.9% in 2002, 45.7% in 2011-15; non-Hispanic black male: 63.3% to 58.6%

–of these, the differences in females in 2011-15 were not statistically significant; though the difference/decrease in non-Hispanic black males was significantly higher than the others

–assessing sexual activity by family structure at age 14: for females, a significantly lower % were sexually experienced if they lived with both parents (36.8% vs 50.8%) and for males (39.4% vs 51.9%); for males, if their mothers gave birth to first child by age >=20 (39.3% vs 56.7% if mothers younger). Also for males, less sexually experienced if mother had at least some college vs high school diploma or GED (41.0%​ vs 46.7%)

–by age: males more likely than females to have sex younger (age 15-16). Though probabilities were the same by age 17

–partners for first sexual experience: 74.1% of females but 51.1% of males were “going steady” with their partner; 13% of females and 27.3% of males with “just friends” (the latter especially true with younger teens)

–reasons for not having sex: most common: religion/morals (35.3% of females, 27.9% of males), then “not found right person yet” 21.7% females, 28.5% males; then “don’t want to get pregnant” 19.3% females, 21.2% males

–no change from 2002 in terms of % of teens who have had sex in past 3 months, though older teens (18-19 yo) were twice as likely as those 15-17.

 

–female teenager use of contraception at first sex:

–increased from 74.5% in 2002 to 81.0% in 2011-15, though lowest in non-Hispanic black teens at 62%, and higher in Hispanic (79%) and non-Hispanic white (87%) teens; overall, mostly using condoms (66.4% in 2002, increasing to 74.6% in 2011-15)

–dual protection (condom plus pill) also increased significantly from 13.1% in 2002 to 18.5% in 2011-15

–overall 5.8% of females had a long-acting reversible method (IUD in 2.8% or implant in 3.0%) in 2011-2015

–male teenager use of contraception at first sex:

–condom use increased from 70.9% in 2002 to 79.6% in 2006-10 and remained stable at 76.8% in 2011-2015

–emergency contraception use has increased significantly from 2002 (8% of female teens who ever used it) to 2011-15 (23%)

–no change in ever using condoms (97%), withdrawal (60%), pills (56%), depo-medroxyprogesterone (17%)

–feelings about hypothetical pregnancy (which does correlate with risk of teen birth, pregnancy risk behaviors): in 2011-15, more females would be very upset (60.5%) vs males (46.1%)

–teens who have sex at an earlier age are not only less likely to use contraceptives at time of first sex, but also at the last sex as well.

 

Commentary:

–although there are lots of statistics above, the report has even lots more….

–it is notable that 81% of females used contraception the first time they have sex, condoms were used by 77% of males the first time they have sex

–overall trends seem to confirm some decreases in sexual activity overall and increase in contraceptive usage since 1988, aligning with the observed decrease in teen pregnancy in the early 1990s (as above). though the contraceptive use largely plateaued or only decreased slightly since 2002, the types and effectiveness of contraceptives used has changed

–there is a general trend to promote long-acting reversible contraceptives (IUDs implants) in adolescents (eg, see https://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Adolescent-Health-Care/Adolescents-and-Long-Acting-Reversible-Contraception ), and there is dramatically increasing use of emergency contraception

–one important potential utility of all of these statistics is to help us clinicians and public health people focus on teens where the statistical predictors point to those at highest risk of not using contraceptives or becoming pregnant (eg. family and social situation, education, age of first sex, ethnicity/race…)

 

–but, as noted in commentary after the first article, there are real concerns about the future, especially with access to high quality, affordable care (see above)

Primary Care Corner with Geoffrey Modest MD: Yoga for chronic low back pain

26 Jun, 17 | by gmodest

​​by Dr Geoffrey Modest

A recent community-based study of chronic low back pain found that yoga was non-inferior to physical therapy for function and pain (See doi:10.7326/M16-2579).

Details:

— 320 predominantly low income adults with nonspecific chronic low back pain were enrolled in a 12 week, single-blind, 3 group randomized trial, with a 40 week maintenance phase.

— Mean age 45, 60% female, 18% non-Hispanic white/58% non-Hispanic black/14% Hispanic, 32% earned college degree or higher, 45% currently employed, 60% with annual income less than $30,000, BMI 31, mean back pain intensity 7 (on scale of 11), RMDQ score 15 (score range 0 to 23, higher score means worse function), 70% on pain medications (52% NSAIDs/35% acetaminophen/20% opioids), comorbidities of hypertension 35%/neck pain 30%/pulmonary disorders 25%/diabetes 18%/depression 20%. [the Roland Morris Disability Questionnaire (RMDQ) of 15 and pain intensity score of 7 reflect moderate to severe pain]

— the study was done in an academic safety net hospital and 7 affiliated federally-qualified community health centers in ethnically diverse neighborhoods in Boston

— the 3 groups were:

— 12 weekly 75-minute yoga classes, each class beginning with relaxation and meditation exercises, yoga breathing, and yoga philosophy; then yoga poses; and then relaxation. 30 minutes of daily home practice were encouraged, with patients getting a DVD, manual, and take-home yoga supplies

— fifteen 60-minute PT visits, including treatment-based classification, graded exercise, and screening for fear-avoidance beliefs

— an educational book (the Back Pain Helpbook) and newsletters on low back pain self-management, stretching, strengthening, and the role of emotions and fear-avoidance

— the maintenance phase compared yoga drop-in classes vs home practice; or PT booster sessions vs home practice

— primary outcomes: back-related function as measured by the RMDQ, and pain measured by an 11 point scale, both measured at 12 weeks. Prespecified noninferiority margins were 1.5 on the RMDQ scale and 1.0 for the pain scale.

— Secondary outcomes included pain medication use, global improvement, satisfaction with intervention, and health-related quality of life

Results:

— median yoga attendance was 7 classes, median PT attendance was 7 appointments.

— home practice was reported by 75% of yoga participants (for median of 27 minutes) and 64% of PT participants (median of 4 exercises, 4 days per week)

— fewer than half of the participants met the predefined adherence goal: at least 9 yoga or 11 PT sessions

— of 59 participants randomly assigned to yoga drop-in classes during the maintenance phase, 53% attended at least one class (median 13); of 54 participants randomly assigned to PT booster sessions, 56% attended at least one (median 2)

— primary outcomes:

— improvement in RMDQ for yoga -3.8, which was noninferior to PT, -3.5. Education was -2.5

— decrease pain for yoga was -1.7, which was noninferior to PT -2.3. Education was -1.4

— yoga and PT were not superior to education at 12 weeks, however both yoga and PT were more likely than education to have a clinically meaningful response in RMDQ (which they define as 3.0 points), but yoga did not reach quite reach their meaningful cutpoint of 2.0.

— secondary outcomes:

— greater than 30% reduction in RMDQ: 48% yoga vs 37% physical therapy vs 23% education

— greater than 30% reduction in back pain 35% yoga vs 43% physical therapy vs 25% education

​– at 12 weeks, use of any pain medication was 55% yoga (33% acetaminophen, 33% NSAIDs, 23% opioids) vs 54% using any pain medication with PT (22% acetaminophen, 43% NSAIDs, 14% opioids) vs 75% using any pain medication in the education group (39% acetaminophen, 48% NSAIDs, 18% opioids)

— self-rated global improvement: 34% improved with yoga vs 42% PT vs 21% education

— satisfaction with intervention: 43% very satisfied with yoga, 50% with physical therapy, 21% with education

–no difference between groups for either SF-36 physical health score or SF-36 mental health score [Short Form-36’s are validated questionnaires]

— in patients who were adherent to the protocol, mean RMDQ changes at 12 weeks were: -4.64 yoga, -5.7 PT, -2.74 education; clinically meaningful improvements in RMDQ in those adherent to the protocol occurred in 57% for yoga, 56% PT, 21% for education. For pain intensity 12 weeks, -2.1 for yoga, -2.6 or PT, -1.34 education, with clinically meaningful pain improvement were present in 50% for yoga, 52% for PT, and 14% with education

— in the maintenance phase, RMDQ or pain changes did not differ significantly between yoga drop-in and yoga home practice, or between PT booster sessions and PT home practice.

— Adverse effects were mild, self-limited joint and back pain.

Commentary:

— as we all know, chronic low back pain is both extraordinarily common (estimates of 10% of the US adults), costly (total costs, including work loss, exceed $200 billion per year), but has low patient satisfaction with treatment.

— Physical therapy is the most common evidence-based, reimbursable, nonpharmacologic therapy prescribed by clinicians. There are several studies suggesting that yoga also helps. So, this study is helpful for showing that yoga is on a par with physical therapy in decreasing pain and improving function.

–although they found that yoga/PT were not superior to education for both function and pain, there were meaningful improvements for RMDQ with yoga and both for PT, the improvements were maintained after one year (which unexpectedly was irrespective of whether the patients had ongoing yoga or PT booster classes or not), and the likely explanation of these results was the low adherence rates to the yoga/PT programs. Looking at the adherent patients, the results were dramatically more impressive for RMDQ and pain, as highlighted above.

— I should also note that several important findings  (eg, use of medications, patient satisfaction, >30% improvements) were also really impressively better with yoga/PT

–this study was particularly useful to many of us because it focused on community-based care in poor and non-white areas, in which there has been documented increased incidence of pain and disability from low back pain, fewer referrals for specialists, and less-intensive rehabilitation for occupational back injuries. Yoga classes, however, are less available and less used in poorer and nonwhite areas

–unfortunately, the use of yoga was not able to decrease the use of opioids much, though other pain meds were decreased

 

so,

–yoga may well be a useful ​aid for patients with chronic low back pain

–yoga may also be cheaper for patients who have high copays for PT

–and, yoga instruction is readily available to patients with internet connection or DVD players. My overwhelming experience is that patients who do PT for back pain (or other symptoms) rarely continue with significant home-based exercises to maintain their PT benefits, frequently requiring repeat PT programs in the future and/or persistent pain/functional loss. Perhaps one of the difficulties for patients is transitioning from the array of PT therapies (eg using expensive exercise machinery or treatments unavailable at home) to the home-based, low-tech PT exercises.  Yoga might provide a more fluid transition from office-based yoga training and performance, since patients continue to do the same thing at home.

Primary Care Corner with Geoffrey Modest MD: Low use of buprenorphine in youth

22 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent large-scale analysis from health insurance claims found that under one-quarter of adolescents and young adults with opioid use disorder (OUD) received either buprenorphine or naltrexone (see doi:10.1001/jamapediatrics.2017.0745)

 

Details:

— retrospective cohort study based on reviewed insurance claims of 9.7 million youth aged 13 to 25; they identified 20,822 with a diagnosis of OUD 2001 to 2014, and matched them with those receiving prescriptions for either buprenorphine or naltrexone within 6 months of the OUD diagnosis. They used the national commercial insurance database Optum, which has inpatient, outpatient, emergency dept and pharmacy claims from large commercial health insurer databases, with members in all 50 states.

— In those with OUD: 66% male, 82% non-Hispanic white/6% Hispanic/2% non-Hispanic black or Asian, mean age 21 at 1st diagnosis, 68% urban, neighborhood educational level was rated high 67%/high-middle 20%/low-middle 10%/low 3%, neighborhood poverty level was rated high 6%/high-middle 15%/low-middle 25%/low 54%, region South 42%/Midwest 26%/West 17%/Northeast 15%

— diagnosis of OUD: 3% age 13 to 15/9% age 16 to 17/35% age 18 to 20/53% age 21 to 25

 

Results:

— the rate of OUD diagnoses increased from 0.26/100,000 person-years in 2001 to 1.51/100,000 person-years in 2014, a 6-fold increase

— overall, 26.8% of the youth were dispensed buprenorphine/naltrexone within 6 months of OUD diagnosis, with 89% being buprenorphine and 11% naltrexone (the relative use of naltrexone has increased in the last 5 years)

— medication prescriptions increased from 3% in 2002 (year buprenorphine introduced) to 31.8% in 2009, then decreased to 27.5% in 2014;

— in multivariable analysis (controlling for sex, age at OUD diagnosis, race/ethnicity, geographical region, neighborhood educational level and neighborhood poverty level), adjusted probability of receiving buprenorphine/naltrexone:

— age 13 to 15: 1.4%

— age 16 to 17: 9.7%

— age 18 to 20: 22%

— age 21 to 25: 30.5%

— the above trend had p<0.001 for the difference

— females: 20% vs 24% of males (p<0.001)

— 14.8% non-Hispanic black vs 20% Hispanic vs 23.1 % non-Hispanic white (p<0.001)

​–so, lower likelihood of treatment in younger people, females, non-Hispanic black or Hispanic youth

 

Commentary:

— we are all aware of the huge medical and social issues associated with OUD, including mortality (now surpassing that of motor vehicle accidents), diseases (increases in hepatitis C, HIV), mortality, costs to the system (ER and hospital use) and huge social disruptions

a prior blog highlighted the tripling of opioid deaths from 1999 to 2014

and another blog specifically reported youth substance use and trends in 2013

— as noted in the current article, prior studies have found that 2/3 of people in treatment for OUD began drugs before age 25, and 1/3 before age 18, though only 1 in 12 adolescents and young adults are in treatment

— there have been some important deficiencies in the approach within pediatrics: the American Academy of Pediatrics did not come out with a policy statement recommending the use of pharmacotherapy for OUD until August 2016, though buprenorphine was approved for those >15yo in 2003; and only 1% of the physicians certified to prescribe buprenorphine are pediatricians

— one striking incongruity is the rather unfortunate situation where clinicians can prescribe opiates without specific training, yet they need formal training to prescribe the safest opiate, buprenorphine, one that has a pretty remarkable track record in helping people with OUD

— there was an interesting discordance in the above study between the neighborhood educational level, with 87% being high or high-middle, though poverty levels was only 21% in the high or high-middle range. Not sure what to make of that, though it should be noted that these data were from geographical tracks and not granular data from individuals with OUD. Also the race/ethnicity of the patients is based on the neighborhood characteristics and surname analysis, without the actual patients’ data

— this study only looked at young patients using buprenorphine or naltrexone within 6 months of their initial encounter for OUD. There are some unanswered questions (at least to me) which make it hard to put this in perspective: though only 1/4 of the youth were on these meds at 6 months, how many older patients are on the meds within 6 months of diagnosis??? (I certainly see many adults you do not get into treatment for decades, and then do really well….)  It may well be that the youth with OUD are not ready to get off the opiates that soon after starting. It would be interesting to look at the number in treatment after 1 or more years after starting.

–it is a bit unnerving that the total proportion of youth dispensed buprenorphine/naltrexone peaked in 2009 (32%) and has trended a bit down since (to 28%), given the increasing mortality from opiates, despite the increased numbers of insured people under the Affordable Care Act (which unfortunately may change soon)

— a prior blog reviewed data showing that even appropriate use of prescription opiates in teens is strongly associated with future opioid misuse, even among teens with low pre-opioid likelihood of developing OUD, see   (ie, opioids even given after surgery in younger people seems to create the increased likelihood of OUD later in life)

the blog raises concerns about naltrexone, given the very limited studies on it. The blog also comments on how the drug company is aggressively lobbying congress and specifically the trump administration to promote naltrexone, despite this paucity of scientific evidence (which the drug company seems not to be interested in pursuing)

 

so,

–this article highlights both this dramatic 6-fold increase in documented OUD in youth over the past 15 years (part of which may be our heightened awareness of the issue, but it is pretty clear that things are a whole lot worse), as well as the fact that such a small percentage of youth are involved in treatment.

— but, I think part of the issue is national stigmatization of those with OUD, which may be responsible at least in part for requiring clinicians to have special training/licenses to prescribe buprenorphine (as opposed to naltrexone), despite its documented safety and effectiveness. This problem with buprenorphine is likely to be exacerbated by tom price, the head of Dept of Health and Human Services in the US, who is pushing for naltrexone, as noted in above blog. Removing constraints on prescribing buprenorphine would not only further legitimize its use but also make it much more available to patients in need

–and part of the problem is our medical culture, which abetted and fueled the current opioid crisis by pushing more aggressive treatment of pain in the 1990s (and this was fed into/strongly promoted by industry, and specifically Purdue, maker of oxycontin, and pusher of “pain as the fifth vital sign”). Yet now one area of the medical culture has played a role in minimizing aggressive OUD treatment (eg, the Am Acad of Pediatrics, not dealing with OUD for more than a 14 years after buprenoprphine became available despite the well-documented dramatic increases in opioid use in youth and its huge social/medical consequences).

 

BMJ Evidence-Based Medicine – Join the Editorial Board

21 Jun, 17 | by Kelly Horwood, BMJ

We are changing the way the journal looks, feels, and operates. In order to do this well, we would very much like your help in delivering relevant, trustworthy, and impactful evidence-based content to as wide a range of frontline health professionals as possible.

 

We are planning to publish original evidence-based research, insights and opinions on what matters for health care, whilst focusing on the tools, methods, and concepts that are basic and central to practising evidence-based medicine. Our plan includes exciting developments in the types of articles that debate the uncertainties and controversies in evidence, and the research methods that educate and inform practice.  Our new clinical spotlight section will strive to disseminate relevant research: saving you time and improving your practice.

 

We are looking for health professionals and EBM researchers who are interested, and motivated, to enhance the practice and understanding of evidence-based healthcare.

We want BMJ Evidence-Based Medicine to be the go-to journal for solving the evidence translational problems that currently prevents uptake of evidence into practice.

 

If you would like to be part of the debate then we would like you to consider becoming an Editorial Board member

 

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Primary Care Corner with Geoffrey Modest MD: Decreasing antibiotic resistance by stewardship program

21 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent systematic review and meta-analysis found that hospital antibiotic stewardship programs significantly reduced the incidence of infections and colonization with antibiotic-resistant bacteria and C difficile infections (see doi.org/10.1016/ S1473-3099(17)30344-4).

 

Details:

–32 studies in a meta-analysis with 9,056,241 in-hospital patient days and 159 estimates of incidence ratios (IRs) of target infections

–studies from 20 countries: US (5 studies), Japan (4), Germany (3), France (3). Most common design was before-after analyses

–most frequent stewardship  interventions:  audits in 59%, implementation of restrictive policies in 47%, co-implementation of stewardship programs with infection control measures (mostly hand hygiene) in 25%

 

Results:

–antibiotic stewardship programs reduced the incidence of and colonization with:

— multi-drug resistant gram-negative bacteria: 51% reduction; IR 0.49 (0.35-0.68), p<0.0001

–specifically, a 43% reduction in carbapenem resistance; IR 0.57 (0.40-0.81), p=0.0018; this was especially true for carbapenem-resistant Acinetobacter Baumannii, 56% reduction, and P aeruginosa, 29% reduction

— extended-spectrum b-lactamase-producing gram-negative bacteria: 48% reduction; IR 0.52 (0.27-0.98), p=0.04

— methicillin-resistant staph aureus (MRSA): 37% reduction; IR 0.63 (0.45-0.88), p=0.007

— c diff infections: 32% reduction; IR 0.68 (0.53-0.88), p=0.003

–antibiotic stewardship programs were more effective when implemented with hand-hygiene interventions: 66% reduction; IR 0.34 (0.21-0.54), p<0.001; in those without hand-hygiene interventions, there was a 17% reduction; IR 0.83 (0.71-0.98), p=0.03

–no difference in vancomycin-resistant enterococci, or quinolone-resistant and aminoglycoside-resistant gram-negative bacteria

–in terms of sites in the hospital:

–59% reductions in hematology-oncology departments

–23% reduction in ICUs

–22% reduction in medical departments

–in terms of types of stewardship interventions:

–antibiotic cycling: 51% reduction in antibiotic resistance; IR 0.49, p=0.003

–audits and feedback: 34% reduction; IR 0.66 p=0.0006

–antibiotic restriction: 23% reduction; IR 0.77, p=0.0003

–interventions generally became more effective over time: 10% reduction for 1980-2000; 21% reduction for 2001-5; 32% reduction for 2006-13

 

Commentary:

–various types of antibiotic stewardship programs have had success in other studies, including use of empirical therapy as suggested in treatment guidelines, de-escalation of therapy to more targeted/narrower spectrum antibiotics, switching from IV to po antibiotics, restriction of antibiotics, and bedside consultation

–a review of their table of the studies involved in the above meta-analysis shows that the various interventions in the studies pretty consistently decreased some infections

–it is noteworthy to reinforce the pretty striking effects of hand-hygiene in preventing bacterial resistance, including both MRSA and antibiotic-resistant gram-negatives. the hand-hygiene strategies used varied from: education, to replacement of handwashing with alcohol-based hand rubbing, to substitution of hand-directed soap dispensers with elbow-directed soap dispensers.

–other studies have shown decreases in mortality and antibiotic costs through stewardship programs.

–and, other studies have shown that using guideline-based empirical therapy was associated with a 56% reduction in mortality and using de-escalation strategies led to a 35% mortality reduction

–one key feature in the meta-analysis  probably was the high compliance/involvement of physicians, educational feedback, and close relationships between physicians and the stewardship team (the authors did not comment on non-physicians).

–this meta-analysis was limited by many issues, including study heterogeneity, difficulty in culling out single interventions in more detail, the potential for secular trends/differences over time, the inability to target the different specific hand-hygiene measures, and significant differences in individual study quality (2 studies were high quality, 26 moderate, 4 low)

so, I bring up this article for a few reasons, though it does not directly apply to outpatient practice (other than that we get the output of resistant bacterial strains as they migrate from the hospital to the community):

–there may be some lessons we could apply directly to primary care, eg:

–using more guideline-based antibiotic therapies

–being more diligent specifically in limiting antibiotic use for evidently viral illnesses (a large % of antibiotic use, as per blogs below)

–using more targeted and narrower-spectrum antibiotics (eg, avoiding cipro for UTIs)

​–spending more time discussing the potential consequences of antibiotic overuse with patient

​–making sure that patients understand the importance of taking complete courses of antibiotics when indicated

–making sure we optimize hand hygiene

​–and perhaps implementing a stewardship plan: the easiest plan, with pretty strong data above, would likely be simply audit and feedback to providers on a regular basis

–and, i think it is important for us to understand the gravity of the antibiotic-resistance issue and the likely development of increasing numbers of untreatable infections, and not just the weird ones that hang out in hospitals, but even just e. coli or n. gonorrheae (eg see blog  )

for blogs going into more detail on some of these issues:

(see here for the slew of blogs on antimicrobial resistance,  and see below for some more specific ones)

— this blog found that true penicillin allergy is really uncommon, and that we may therefore be using broad-spectrum antibiotics more often than necessary

this one reviewed ​the latest WHO categorization of resistant bacteria of international concern, and also has a general assessment of the lack of drug company investments in new antibiotics, and that the major use of antibiotics and development of resistance is actually from industrial non-therapeutic use of antibiotics in livestock. there are also links to other blogs on the effects of antibiotics on the microbiome and the significant prescribing of antibiotics for human  nonbacterial conditions (eg URIs, acute rhinosinusitis, pharyngitis, bronchitis)

and this one reviewed the WHO guidelines on treating sexually-transmitted infections in this era of antibiotic resistance

Primary Care Corner with Geoffrey Modest MD: ?Add PPI to aspirin in elderly

20 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A prospective population-based cohort study of patients with vascular disease and on antiplatelet therapy (mainly low-dose aspirin) found a dramatic increase in the risk of bleeds in those over 75 years old, raising the question of whether we should be using proton-pump inhibitor (PPI) prophylaxis (see doi.org/10.1016/S0140-6736(17)30770-5)

 

Details:

— 3166 patients with vascular disease (defined as a 1st TIA, ischemic stroke, or MI and placed on antiplatelet therapy) in the Oxford Vascular Study from 2002 to 2012 were followed until 2013. 50% of the cohort were greater than 75 years old

— for the subgroup of patients < 75 years old:

— mean age 61, 65% male, 32% ischemic stroke/30% TIA/21% NSTEMI/17% STEMI, 97% on aspirin/3% nonaspirin antiplatelet therapy

— for those > 75 years old:

— mean age 83, 43% male, 42% ischemic stroke/27% TIA/23% NSTEMI/8% STEMI, 95% on aspirin/5% nonaspirin antiplatelet therapy

— the predominant aspirin formulation was 75 mg enteric-coated aspirin

 

Results:

— there were 405 1st bleeding events (187 major bleeds) during 13,509 patient years of follow-up in the cohort, at an average annual risk of 3.36%:

— 218 gastrointestinal

— 45 intracranial

— 142 other

— risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age, particularly in those > 75 years old, with no increase with age in patients < 70

— for those >75 yo vs <75 yo:

— major bleeding overall, HR 3.10 (2.27-4.24), p<0.0001 [ie, more than 3-fold the risk]

— fatal bleeds, HR 5.53 (2.65-11.54), p<0.0001

— major upper GI bleeds, HR 4.13 (2.60-6.57), p<0.0001; and fatal GI bleeds, HR 10.26 (4.37-24.13), p<0.0001.

— The annual risk of major bleeds increased steeply after age 70, reaching 4.1% at age 85 or older, with a similar pattern for both life-threatening and fatal bleeds. Those > 75 yo had more severe bleeds in those younger, p<0.0001. The outcome for nonfatal bleeds was also worse in the older group.

— Also, the proportion of those who survived extracranial bleeds which resulted in new or a sustained increase in disability increased with age, OR 12.8 (4.5-36.6), p<0.0001, comparing those > 75 vs <75 yo, especially in those with upper GI bleeds

— this analysis was similar if those on dual antiplatelet treatment (e.g. aspirin plus clopidogrel) were excluded

— the association of major bleeding with age were independent of sex, history of vascular disease, vascular risk factors, and history of peptic ulcer disease

— the absolute risks of major bleeding vs ischemic events increased with age. In the younger cohort this ratio was similar to those in prior aspirin trials. But the ratio increased from 0.19 in those younger than 75, to 0.32 in those 75 to 84, to 0.46 in those older than 85 [ie, the risk of major bleeds estimated to be attributable to antiplatelet treatment was approaching that of prevented ischemic events].

— The estimated number needed to treat (NNT) with routine PPIs to prevent one disabling or fatal upper GI bleed over 5 years would be 338 for individuals < 65 years old, but only 25 for individuals > 85 years old. The NNT to prevent one major upper GI bleed at 5 years was 80 for patients younger than 65, 75 for patients 65-74, 23 for patients 75-84 and 21 for patients greater than 85.

 

Commentary:

— given the high prevalence of vascular disease in people over 75, 40-66% of individuals in the US and Europe take aspirin or other antiplatelet drug for secondary prevention of vascular disease (and this does not include primary prevention use of aspirin!!!!). Guidelines in general do not recommend taking PPIs regularly, though a meta-analysis of randomized PPI trials vs placebo in patients on antiplatelet drugs, mostly aspirin, found a 74% reduction in upper GI bleeding (this was the number they used in estimating the preventive efficacy of PPIs above).

— The general basis for recommendations for use of antiplatelet agents is largely based on trials done in people < 75 years old (the mean age was 63, and most were < 75 yo).

— As a perspective in this study, PPIs would presumably only prevent upper GI  bleeds, though 60% of all bleeds and 48% of major bleeds in the above study were non-upper GI bleeds

— assumptions in the above study, as noted by the authors, are that the efficacy of PPIs would be similar for the prevention of any bleed vs major bleed, similar at different ages, and remain consistent over time.

— I am very concerned about the role of H Pylori infections in predisposing patients to upper GI bleeds when they are on NSAIDs.  An article in 1997 changed my practice to test and treat people prior to starting regular NSAID therapy (see Chan FKL Lancet 1997; 350: 975, which found that patients about to begin longterm NSAID therapy, had endoscopy, and those found to have asymptomatic H Pylori infection were then were randomized to either naproxen 750mg/d vs triple H Pylori therapy and then naproxen 750 mg/d, finding that on repeat endosopy 8 weeks later, 26% had ulcers in the naproxen only group whereas 3% had them after successful H Pylori treatment). Subsequently the 2008 Expert Consensus document by the Am Heart Assn and Am College of Gastroenterology recommended: “Testing for and eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy.”  (see JACC 2008; 52: 1502). And another more recent article finding that those on low-dose aspirin who had H Pylori infection which had  been eradicated had recurrent GI bleeds at the level of  average-risk patients (see Chan FKL. GASTROENTEROLOGY 2013;144:528–535​)

 

So, as per many prior blogs, I am concerned with long-term, wide-scale use of PPIs, in terms of significant adverse effects, as well as their profound effects on the microbiome. Given the rather compelling data from this study, it would be really great to have a randomized controlled trial in patients for both primary and secondary atherosclerotic disease prevention with aspirin, comparing PPI vs H2 blocker (fewer adverse longterm effects than PPIs) vs placebo, looking at both major GI bleeds as well as comparing them to the incidence of thromboembolic events. And, as per above comment, it would be great to either exclude those who were H Pylori positive, or treat them prior to aspirin therapy. My own practice in general, as mentioned in prior blogs, is to test and treat H Pylori infections, given their profound frequency in my patient population and the association with stomach cancer (I have had several older patients die from stomach cancer, which might have been prevented if H Pylori were diagnosed and treated earlier: eg see here ). Besides, it is always a tad unnerving when we have to prescribe a medication (which is not entirely benign) to counteract the effects of another medication.​ But, based on the study, it does seem reasonable to consider a PPI in those greater than 75 years old and on aspirin therapy.

Primary Care Corner with Geoffrey Modest MD: Canagliflozin decreases macrovasc disease???

19 Jun, 17 | by gmodest

by Dr Geoffrey Modest

Another study assessed the role of a sodium-glucose co-transporter 2 inhibitor, this time canagliflozin, and its effects on cardiovascular and renal outcomes in patients with type II diabetes (see DOI: 10.1056/NEJMoa1611925 ). A drug company supported study.

Details:

— this report involved 2 trials with 10,142 participants with type II diabetes and high cardiovascular risk, randomized to canagliflozin vs placebo, followed a mean of 188.2 weeks. All had HgbA1c between 7 and 10.5%, had a history of symptomatic atherosclerotic cardiovascular disease, or were at least 50 years old and had 2 or more risk factors (which included diabetes of at least 10 years duration). Patients were from 667 centers in 30 countries. 96% participants completed the trial.

— mean age 63, 36% women, mean duration of diabetes 13.5 years, 78% white/13% Asian/3% black, 18% current smoker, 90% history of hypertension/14% heart failure/56% CAD/19% cerebrovascular disease/21% peripheral vascular disease (66% overall had a history of cardiovascular disease), 2% amputation, BMI 32, blood pressure 137/78, A1c 8.2%, 70% with normal albuminuria/22% microalbuminuria/8% macroalbuminuria

— baseline diabetes therapy: 50% insulin/43% sulfonylurea/77% metformin/4% GLP-1 inhibitors/12% DPP-4 inhibitors

— the 2 studies overall were similar, though in one study patients received canagliflozin 300 mg vs canagliflozin 100 mg vs placebo, the other canagliflozin 100 mg with an optional increase to 300 mg vs placebo

— primary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.

Results:

— for those on canagliflozin (vs placebo):

— the use of other antihyperglycemic agents was 9.3% lower.

— HgbA1c -0.58%, BMI -1.60, blood pressure -4/-1 mmHg (p<0.001 for all comparisons). LDL and HDL were higher with canagliflozin, though the ratio was similar

— the primary outcome was lower with canagliflozin, 26.9 vs 31.5 per 1000 patient-years, a 14% decrease with HR 0.86 (0.75-0.97), p<0.001 for noninferiority, p=0.02 for superiority

— these outcomes were broadly consistent across prespecified subgroups, though those on baseline diuretics did significantly better (34%, HR 0.66, p<0.001) and those not on diuretics had a trend to doing worse

— the pre-specified secondary renal outcomes (progression of proteinuria with >30% increase and a change from either normoalbuminuria to microalbuminuria or from micro to macroalbuminuria) overall were not statistically significant, however there seemed to be a possible benefit of canagliflozin in terms of progression of albuminuria, HR 0.73 (0.67-9): regression of albuminuria with HR 0.60, as well as for the composite outcome of the sustained 40% reduction in eGFR plus need to renal replacement therapy plus death renal causes, HR 0.60 (0.47-0.77)

— adverse reactions: overall 7% less common in those on canagliflozin, but of note there were twice the number of amputations, 6.3 vs 3.4 participants per 1000 patient-years, HR 1.97 (1.41-2.75), in 71% at the level of the toe or metatarsal, and especially those with a prior history of amputation or peripheral vascular; fracture risk was also higher, occurring in 15.4 vs 11.9 per thousand patient years, p=0.02; and, as per prior studies of SGLT-2 inhibitors, there were more cases of osmotic diuresis, volume depletion, and mycotic genital infections in women in those on canagliflozin, though not urinary tract infections.

Commentary:

–reviewing their graphs, there were several major differences in the groups of canagliflozin:

–the HgbA1c was significantly lower, was down to 7.5 by week 26, slowly increased to 7.8 by week 150, and ultimately to around 8.0 by week 300. placebo was pretty consistently around 8.2-8.3

–mean weight decreased to 87kg with canagliflozin but remained around 89-90 kg with placebo

–blood pressure was 131/74 with canagliflozin but 136/76 with placebo

–the graphs for cardiovascular events:

–deaths from cardiovascular causes, nonfatal MI or nonfatal stroke: curves separated at around 52 weeks of treatment, then paralleled after 104 weeks

–death from cardiovascular causes: nonsignficant. curves initially separated favoring canagliflozin then merged together after 260 weeks

–nonfatal stroke: also nonsignificant and similar to cardiovascular deaths

–nonfatal MI: also nonsignificant, though did separate after 104 weeks and remained separate

–other outcomes:

–death from any cause: nonsignificant

–heart failure hospitalizations: signficantly better with canagliflozin, HR 0.67 (0.52-0.87) with separation early, by 26 weeks

–renal: clear benefit beginning by 78-104 weeks for progression of albuminuria and the composite of 40% reduction in eGFR, requirement for renal replacement therapy or death from renal causes [though it seems that lowering A1c itself seems to be renoprotective from many studies, and those on canagliflozin had lower A1c levels!!!]

–it is unclear how much of the benefit from canagliflozin is related to the protective effects of this drug, given the substantial differences in HgbA1c, weight and blood pressure. the change in renal outcomes would largely be expected from these differences, as per many prior studies (unfortunately the authors did not compute the expected effect attributable to these A1c changes, but they would certainly go a long way to explaining the differences). and the differences in macrovascular outcomes (their primary outcomes) similarly may be explained largely by these differences in the constellation of better A1c, blood pressure, and weight loss in the canagliflozin group

–also, there is no comment in the article or the supplementary materials about the differences in treatment in the placebo group: they comment that the use of other antihyperglycemic agents was 9.3% lower with canagliflozin but do not comment on what additional meds were used in the placebo group. was it potentially harmful agents (eg rosiglitazone)? more sulfonylureas (which do not seem to help and may hurt cardiovascular outcomes)? more GLP-1 agonists (which would make their results more impressive, given that these do seem to be cardioprotective)

–and it is concerning about the increase in both amputations and fractures with canagliflozin.  Bones do not seem to fare well.

–also, see prior blogs on another SGLT2 inhibitor empaglifozin, where I found the study also quite flawed. And, it is important to remember, these SGLT-2 trials were both drug-company sponsored. and, it would not be so surprising to find that these trials are designed to achieve the results that the drug companies would like….  for example, they could have designed this canagliflozin trial so that the A1c levels in both the drug and placebo groups matched!!!! we could then sort out how much of the problem was related to the A1c differences and how much to the drugs used (they would also need to describe what drugs were used….)

so, how to proceed?

–these SGLT2 inhibitors possibly do decrease cardiovascular events (at least this has been shown for 2 different ones, though I think both studies are pretty flawed, as above). it should be kept in mind that  the FDA does warn about ketoacidosis and severe urosepsis with these drugs (see https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm​ ), and there are reports of acute kidney injury as well as a pretty high incidence of genital mycotic infections.​

–i personally am still more impressed with the studies on GLP-1 agonists. they seem to be cardioprotective, I am consistently shocked at how well they work in lowering A1c levels, and they are quite targeted (the most common problem I have seen is GI, though a few cases of itchy rash/apparent allergy to one of them, though subsequent use of another was well-tolerated). And, they have been around for a long time ( exenitide has been used in Europe for >10 years).

Primary Care Corner with Geoffrey Modest MD: Does glucose home-monitoring help???

15 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent article added to some prior literature suggesting that glucose self-monitoring is not so effective in type II diabetics not on insulin (see doi:10.1001/jamainternmed.2017.1233 ).

 

Details:

— 450 patients were enrolled in this pragmatic, open label randomized trial, of which 418 completed the final visit. All were in established primary-care relationships in North Carolina, had a hemoglobin A1c between 6.5% and 9.5%, and were randomized into one of 3 wings: no self-monitoring of blood glucose (SMBG), once daily SMBG, or once daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter that were intended to educate and motivate patients with an algorithm that took into account the blood glucose value, time of day, and relationship to food intake.

— Median age 61, 46% male, 33% black/62% white, 60% high school or some college/34% college or higher, BMI 33, 38% with low health literacy, mean duration of diabetes 6 years, 3 comorbidities, current use of SMBG 75%, diabetic meds were metformin 80%/sulfonylurea 36%/TZD 5%/DPP-4 inhibitor 9%

— baseline hemoglobin A1c 7.6%

— Primary outcomes were: hemoglobin A1c level and health-related quality of life at 52 weeks

 

Results:

— testing adherence declined in both of the SMBG groups (though more so in the group with messaging!): daily testing overall going from around 95% initially to 60% at 12 months; for the no SMBG group, 24% tested at least a few times/month and only 9% tested less than once/month

— follow-up hemoglobin A1c’s were:

— no SMBG: baseline 7.52, follow-up 7.55

— SMBG, no messaging: 7.55, follow-up 7.49

— SMBG, with messaging: 7.61, follow-up 7.51

— there was no significant difference between hemoglobin A1c levels across all 3 groups (p=0.74), with estimated adjusted mean A1c difference:

— SMBG with messaging vs no SMBG: -0.09% (-0.31% to 0.14%)

— SMBG vs no SMBG: -0.05% (-0.27% to 0.17%) [as a reference here, a 0.5% difference (10x this difference) is considered to be clinically significant]

— there was no significant difference in health-related quality of life.

— there was no significant difference in adverse events including frequency of hypoglycemia, healthcare utilization, or insulin initiation

— there was no significant difference in almost all of the secondary outcomes, including the diabetes empowerment scale, diabetes treatment satisfaction scale, and the communication assessment tool.

 

Commentary:

— prior studies have been mixed on the role of SMBG in non-insulin using patients, though more than 75% do regular SMBG

–there were several limitations of the study, many noted by the authors: this study really reflected whether it was useful to continue SMBG, since most patients had already been doing so (ie, not whether initiating SMBG mattered for those not doing so); and there was a selection bias in that all participants were willing to be randomized into a group not using SMBG. Also, about 40% in the daily testing group stopped doing so (though not sure what that means, since they don’t say whether this is decreasing testing to 6x/week or 1x/month…)

 

the bottom line here: I think that it can be useful to have some home-based glucose monitoring for a few reasons, including fuller details on blood sugar swings during the day, with the potential:

–to elucidate to the patient what tends to make the blood sugar go up or down (eg, it was the last meal with rice which raised the blood sugar, or doing exercise lowered it….). This real-time feedback can well inform the patient on what lifestyle issues either improve or worsen blood sugars, leading to appropriate tweaking of them. in my experience, after suggesting to patients that they monitor their blood sugar 1-2 hours after a meal, that the patients are better able to identify triggers to higher blood sugars. and, sometimes, they are able to modify their diets

–to adjust medications to cover these higher or lower levels, if lifestyle changes would not help

–but I think that the main message from this study, as well as prior ones, is that our primary focus as clinicians should not be primarily to strongly encourage/berate patients about checking their blood sugars at home, but to focus on lifestyle changes and medication adherence. as I have mentioned in prior blogs, I think that diabetes treatment is one of the hardest issues I deal with in clinical medicine. it brings to the fore the multitude of issues and obstacles to treating this complicated disease, including the difficulty in eating well/exercising (access to good foods, ability/time to cook healthy meals, access to good exercise venues including safe streets to walk on/time to do so in our overprogrammed lives, and generally competing with a culture and with persuasive advertising to eat poorly, sit at home watching TV, work 2 jobs to survive, etc, which are perhaps the most important underpinnings for our diabetes epidemic.)  these are the hard issues for our patients, and i think the primary ones to focus on. And really focusing on  the importance of SMBG​ can actually dilute/divert this pivotal message of the importance of lifestyle changes.

Primary Care Corner with Geoffrey Modest MD: Monitor BP effects by ABPM?? SPRINT trial

14 Jun, 17 | by gmodest

by Dr Geoffrey Modest

The SPRINT hypertension study assessed different blood pressure targets on clinical outcomes, finding the lower the pressure, the better. A subsequent ambulatory blood pressure substudy of SPRINT looked at the relationship between the achieved ambulatory versus clinic-based blood pressures (see DOI: 10.1161/HYPERTENSIONAHA.116.08076.)

 

Details:

— the SPRINT study randomized patients to aggressive vs less aggressive blood pressure control, achieving a systolic of 121 mmHg versus 136 mmHg, respectively. The primary clinical outcome (MI, acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) was 25% less frequent in those having tighter control. (see here for details)

— in the current ancillary study on ambulatory blood pressure monitoring (ABPM), they performed ABPM at the 27-month study visit in a subgroup of 897 SPRINT participants

— for this ancillary study, mean age 71, 29% female, 66% white/28% black/3% Hispanic, BMI 30, 46% never smoker, 38% nondrinker/26% moderate drinker/10% heavy drinker, 21% CVD at baseline, eGFR 67, LDL 108/HDL 53/triglycerides 100, number of antihypertensive meds at the 27 month visit = 2.9 with 78% on ACE-I/ARB, 60% on calcium-blocker, 76% diuretics, 40% beta-blocker

— at the 27 month clinic visit:

— clinic-based systolic 120 mmHg

— nighttime ABPM systolic 116 mmHg

— daytime ABPM systolic 127 mmHg

— 24-hour ABPM systolic 123 mmHg

 

Results:

— for those on intensive therapy:

— decreased clinic-based systolic BP by 16.0 mmHg

— decreased nighttime systolic BP by 9.6 mmHg

— decreased daytime systolic BP by 12.3 mmHg

— decreased 24 hour systolic BP by 11.2 mmHg

–there was poor agreement in participants between clinic-based systolic BP and daytime systolic ABPM

 

Commentary:

— the role of ABPM continues to evolve, with studies documenting its strong association with cardiovascular and renal clinical events. Data for the last decade or so have pretty convincingly shown that ambulatory blood pressure is more predictive of cardiovascular events than clinic-based blood pressure, leading ultimately to the USPSTF promoting ABPM in their most recent guidelines (see https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/high-blood-pressure-in-adults-screening , and my blog on it )

— One issue with the SPRINT study has been the rather eclectic way they measured the clinic-based blood pressure, reducing its generalizability to our clinical practice (see here which comments on their approach). One advantage of ABPM is that it is an equalizer, where the target blood pressure is pretty reproducible from one ambulatory monitor to another, and does not depend on measuring blood pressure in a clinic setting based on a very structured and likely unreproducible methodology (even without the strict regimen in SPRINT, how many of us check blood pressures after the patient has been resting quietly in a dark room for 5 minutes??)

— Unfortunately, there are relatively limited data on ambulatory blood pressure monitoring as a means to follow up patients with hypertension on treatment. There are some studies which do suggest that it is useful: a Brazilian study (see Salles GF. AchInternMed.2008;168:2340), which looked prospectively at 556 patients with resistant hypertension for 4.8 years, found that ambulatory blood pressure monitoring predicted clinical endpoints, and that clinic-based blood pressure did not. And in fact 40% of those with clinic-based “resistant hypertension” did not even have hypertension on ABPM (adding to the studies finding that even “appropriately” documented clinic-based blood pressure is really a poor predictor, and sometimes pretty irrelevant, especially as compared to ABPM: see here for an array of blogs on this, including the quite impressively documented and  prescient recommendations from NICE in the UK in their 2011 guidelines

 

So, this study adds further to the imperative to use ABPM, especially in those patients with blood pressures near the goal (ie, the patient with 200/110 mmHg can just be treated….). And, though much less well documented (but easier for many) to use home-based measurements. This study helps reinforce the utility of ABPM in those being treated (again, I would assume, especially so if the achieved blood pressure is pretty close to goal: eg the Brazilian study above on refractory hypertension finding no benefit for clinic-based blood pressures did not have granular data, but I would assume that those way above goal continued to need adjustment of their meds independent of the ABPM reading, and those near goal were more likely to be in-range with ABPM even though the clinic-based pressures were high.

 

And, again, this study does raise a pretty basic concern: how often do our accepted clinical approaches (in this case clinic-based blood pressures) not really reflect the reality of actual clinical outcomes, yet are passed down over time and accepted? Which all reinforces the importance of constantly challenging our existing models. Another example which I have commented on recently is with A1c as a surrogate marker for diabetes and macrovascular complications, suggesting that the issue may be less with the A1c achieved than with the medications we choose to put patients on, and it is probably most important to choose ones that have documented cardioprotection (see here )

Primary Care Corner with Geoffrey Modest MD: Opioidsx3, and drug company shenanigans to boot

13 Jun, 17 | by gmodest

by Dr Geoffrey Modest

This is a triple blog on a few recent developments in the opioid world.

  1. The FDA just announced that they are seeking removal of Opana ER, long-acting oxymorphone hydrochloride, “based on its concern that the benefits of the drug may no longer outweigh its risks”. [And certainly many of us thought it was ridiculous to approve it from the start. We have all been through this scene before with oxycontin…].  The FDA found (not so surprisingly) that there was a shift in its route of abuse from nasal to injection after the product was reformulated (it had been reformulated “to make it more resistant to physical and chemical manipulation for abuse by snorting or injecting”….).   This increase in injection use has been associated with outbreaks of HIV, hepatitis C and some cases of thrombotic microangiopathy. And if the company refuses to remove the drug from the market voluntarily, the FDA will formally require its removal by withdrawing its approval. (see see https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm562401.htm​  )

 

  1. the NY Times had an article on 6/10/17 highlighting the increasing role of the internet in buying opiates (they highlight fentanyl), using the “dark web sites” whereby the drugs can be bought anonymously using a special browser, buying the drugs with virtual (untrackable) currencies like bitcoin. A couple of 13-year olds were also highlighted, who had gotten the drugs this way. The reporter commented that “the leading dark net market, AlphaBay, had >21,000 listing for opioids and >4100 for fentanyl and similar drugs from dozens of dealers large and small”. see https://www.nytimes.com/2017/06/10/business/dealbook/opioid-dark-web-drug-overdose.html ​

 

  1. another NY Times article on vivitrol (extended-release injectable naltrexone), suggested lots of drug company shenanigans (see https://www.nytimes.com/2017/06/11/health/vivitrol-drug-opioid-addiction.html ). Basically,

–it is being marketed very aggressively (billboards, buses, subways)

–there are no head-to-head studies with buprenorphine to show its relative effectiveness (and the company seems to not have the least interest in doing those studies)

–it is more expensive than suboxone (eg, 3-fold) [though I should add that naltrexone is an old generic drug, used in the past with some limited success for alcohol dependence, reformulated as an extended release injection but with a dramatic increase in cost]

​–the studies supporting its use are weak: eg a Russian study of 250 patients, where 1/2 failed to stay abstinent for 6 months, though it was better than placebo. And this study and another had very high dropout rates (50% range)

–the new head of Health and Human services, tom price, “ignored widely accepted science” and is praising vivitrol as “the future of opioid treatment”, since the other meds (methadone and buprenorphine​, which work really well) simply “substitute for illicit drugs”

–not shockingly, the drug company Alkermes has been spending millions of dollars in contributions to officials involved in dealing with the opioid crisis (primarily spending money on them vs the usual: doctors and medical associations). it spend $19 million on federal lobbying since the drug was approved in 2010, and $222,521 in political contributions to congress last year

–the company even provides free shots to inmates, with the hope that they will continue to get them when out of jail (??getting people hooked on vivitrol??). And, this has worked pretty well: sales of $58.5M in first quarter in 2017, up 33%, 1/2 from Medicaid, and with huge expansion of Medicaid coverage for it (was 15 programs in 2012 in 9 states, now 450 programs in 39 states).

–and, this promotion of vivitrol may be very harmful: in the setting of the ongoing opioid crisis, and trump’s plan to spend $1 billion for new addiction and treatment programs over the next 2 years, trump and price could really undercut very effective treatments for a largely untested one that appeals more to them, perhaps both financially and ideologically (ie, a lock-step response of “just say no to opioids” without looking at the science or studies)….

 

so,

–it is consistently scary how our system works, in this case likely from greasing the palms of the officials. And it really could lead to vivitrol leapfrogging above buprenorphine or methadone in our political climate. i (and everyone else i know) are generally really impressed with the effectiveness of buprenorphine, including in its long-term use in patients. and it is so safe, as compared to other opiates (and most other meds….).

–getting rid of Opana ER, which many states in the US attempted initially but unsuccessfully​ to block, is a feather in the cap of FDA (it had seemed unlikely that the current FDA leadership would take such a strong position)

–the issue of the dark web is truly scary by making these drugs so much easier to access and so anonymously (eg by kids sitting at home but with internet access).

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