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Primary Care Corner: Decreasing sudden-death in heart failure

13 Jul, 17 | by gmodest

by Dr Geoffrey Modest

A recent meta-analysis found that the risk of sudden death in patients with symptomatic heart failure and reduced ejection fraction (HFrEF) has decreased significantly over the past 20 years (see Shen L. N Engl J Med 2017; 377: 41).
 
Details:
— 12 clinical trials from 1999 through 2014, in which patient-level data were available, included 40,195 patients, but excluded those with implantable cardioverter-defibrillators (ICD)
— Mean age 65, 77% men, 95% with NYHA class II or III heart failure, mean ejection fraction 28% (varied from 23% to 32%), 62% with ischemic heart failure, ACE-I/ARB use was >90%.
— sudden death was determined in 3583 patients
 
 Results:
–Those with sudden death were more often older (low 60s vs mid 60s​), male (low 80% vs mid 70%), had an ischemic cause of heart failure (70% vs 60%), and had worse cardiac function(LVEF 26% vs 29%). There was also minimally lower systolic blood pressure, minimally higher heart rate, minimally worse heart failure symptoms, minimal difference in renal dysfunction, but there was a somewhat more prominent history of myocardial infarction and diabetes in those with sudden death.​ [These were my rough calculations from the supplementary material, no formal calculations done by them]. Also NT-proBNP was higher in those with sudden death, though this was not checked in many of the studies.
— over time, there was a 44% decline in the rate of sudden death across the trials over the 19 years
— the cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial, and 1.0% in the most recent trial. At 180 days the cumulative incidence of sudden death was approximately double that at 90 days, with these same trend of decrease in the more recent trials.
–My review of the individual trials showed a relatively consistent pattern: those with the same heart failure medications in both the control and experimental groups (as in a trial looking at the role of statins or another medication added on) did not show much difference between these groups in terms of sudden death outcomes. However those in which an additional heart failure medicine, either a beta-blocker or a mineralocorticoid antagonist, was added, there generally was a more impressive benefit: ie, maximizing the standard heart failure regimens seems to be beneficial. Only one study used sacubitril/valsartan, finding some added benefit on top of otherwise maximal therapy
— sudden cardiac death was not higher among patients with a recent diagnosis of heart failure than those with longer standing heart failure
 
Commentary:
–This study basically reinforces that maximal therapy for HFrEF patients significantly decreases the risk of sudden death, and to levels where automatically implanting an ICD may not be indicated, particularly in the primary prevention of sudden death. It would be important to determine if there is a subset of those patients who might benefit. One leading contender has been ischemic vs nonischemic cardiomyopathy, where the myocardial scar in those with ischemic cardiomyopathy might be the nidus for ventricular arrhythmias (and, indeed, this study confirmed about a 10% increased risk vs non-ischemic cardiomyopathy).
— Another issue is how long to wait to see the degree of myocardial recovery after the presenting symptoms of heart failure or myocardial infarction. There are studies confirming that multiple drugs and maximal doses lead to more reversal of ventricular remodeling and that the LVEF may still improve over 6 to 12 months after starting treatment (which is significantly longer than the 40 days post myocardial infarction highlighted in the ICD guidelines, suggesting that this time interval may still be too short).
–Current recommendations for ICDs include patients with NYHA class II or III symptoms and LVEF< 35%, independent of cause. However, the recent DANISH trial of patients with nonischemic systolic heart failure showed that adding ICD to maximal medical therapy  led to no difference in total mortality, though there was a reduction in sudden death in those with ICDs (4.3% vs 8.2%). It was notable in the above meta-analysis that only 9% of the patients (3180 in total) had had an ICD implanted and were excluded from this study. Given the low LVEF (median 28%) in these symptomatic patients, so that the majority actually met guideline criteria for an ICD, this 9% number suggests that we clinicians have not been pursuing ICDs very vigorously, even though these patients in the meta-analysis were more likely to have been in cardiovascular centers in big academic medical sites, replete with academic cardiologists….
 
so, 
— This study reinforces that we clinicians are doing quite well in preventing sudden cardiac death by putting patients on maximal heart failure medications.  These meds really work
— As with all interventions, in this case ICD placement, there are real risks for the intervention (in this case: infections, ICD failure, documented decreases in quality of life, and in my experience significant PTSD from patients having been shocked either appropriately are not). Therefore, the more targeted we are at selecting patients for this intervention, the better. Further investigation is warranted to determine those subgroups of patients who really benefit from ICD placement (and those who really do not benefit much and ICDs should be a non-issue).
 
see blog   for a recent review of  the medications for heart failure (including HFpEF), and another which reviewed Medicare patients showing that only 8.1% who qualified for ICDs got them

Primary Care Corner with Geoffrey Modest MD: New colon cancer screening guidelines

12 Jul, 17 | by gmodest

The Multi-Society Task Force of Colorectal Cancer (MSTF), a combo of the Am College of Gastroenterology, Am Gastroenterological Assn, and the Am Society for Gastrointestinal Endoscopy, just published significantly revised guidelines on colorectal cancer (CRC) screening (see doi: 10.1038/ajg.2017.174 ).

 

Details:

–They differentiate between programmatic screening/screening done in an organized system which involves consistent planning, documentation, monitoring of quality, and follow-up (which exists in many industrialized countries, as well as some healthcare plans/medical organizations in the US) vs opportunistic screening, which is largely up to the provider or designee to identify patients who need screening and arrange it

— given the potential for multiple different screens (9 are available), there are various approaches to the patient: offering the patient multiple options, though studies suggest that offering only 2 or 3 preferred options may improve patient adherence; sequential options, where the patient is offered a preferred option 1st, with subsequent options available if the 1st one were declined; or risk-stratified approach, where colonoscopy would be offered to those with a high likelihood or prevalence of advanced precancerous lesions (or potentially patients with higher than average risk, such as older patients, males, those with obesity, diabetes, or smoking), with other tests (eg FIT) being offered to patients at lower risk.

Recommendations:

— offer CRC screening beginning at age 50 in average risk patients (strong recommendation, high quality evidence)

— any of the approaches of multiple screening options, sequential screening options, or risk stratified approaches are reasonable (weak recommendation, low quality evidence)

–cascade of tests:

tier 1 tests: colonoscopy every 10 years, or annual FIT tests. (They prefer the former in sites where there are not good follow-up systems; also may be preferable in men older than 60, and women older than 65 with no prior screening)

–tier 2 tests: CT colonography every 5 years, FIT-fecal DNA every 3 years, flexible sigmoidoscopy every 10 years (or every 5 years)

–tier 3 tests: capsule colonoscopy every 5 years (and do not offer Septin 9)

Other considerations:

— family history:

–CRC in a first-degree relative increases the risk of CRC regardless the age of diagnosis of the affected relative, though the younger the relative, the greater the risk.

–family history of CRC diagnosed <60 years of age or for those with 2 first-degree relatives with CRC or advanced adenoma at any age: colonoscopy began at age 40 or 10 years before the age the relative was diagnosed, whichever comes first, with subsequent colonoscopy every 5 years. FIT testing should be offered to those who decline colonoscopy (a randomized trial showed there was a  trend favoring colonoscopy, but this was not significant).  (weak recommendation, low quality of evidence). prefer colonoscopy

–family history of CRC or advanced adenoma in 1st degree relative diagnosed at age > 60 should have screening beginning at age 40, with normal testing intervals as above  (weak recommendation, very-low quality of evidence). prefer colonoscopy

— age:

–though the incidence of CRC in persons under age 50 is increasing,  the incidence remains low enough that they continue with 50 years old as the starting age overall, for non-African Americans​ (strong recommendation, moderate-quality of evidence).

— in African-American individuals, however, they suggest screening begin at age 45 (weak recommendation, very low quality evidence), since overall they have lower screening rates, higher incidence rates of CRC, early mean age at onset, worse survival and late-stage presentation, and a higher proportion of cancers before age 50. (weak recommendation, very-low quality of evidence): there are a few data suggesting benefit of screening African-Americans before age 50. see yesterday’s blog finding increased interval cancers in black persons soon after a “normal” routine colonoscopy

— age to stop screening: potentially beneficial in persons up to age 86 if they have not previously been screened. Should be put in the perspective of comorbidities and life expectancy. Those with negative screening, especially by colonoscopy, could consider stopping at age 75, though MSTF also suggests the option of  continuing screening until life expectancy is less than 10 years (this is a variation supported by them, as opposed to stopping specifically at age 75, though they did note that this is a weak recommendation with low quality evidence). Consider screening up to age 85 if no prior screening has been done (also weak recommendation with low quality evidence). [But, the risks of colonoscopy increase in those over 75yo (eg, see blog  )]

Commentary:

— adenomas are the precursors of about 70% of CRC’s, and typically take more than 10 years to develop cancer, hence the 10 year suggested interval in those with normal colons and without genetic variants (eg Lynch syndrome). Invasive cancers from adenomas <5 mm is extremely rare, and is <1% in those 6-9 mm in size

— one major concern with adenoma biopsies is the poor-to-moderate interobserver agreement in differentiating high- vs low-grade dysplasia by pathologists, as well as between tubular vs tubulovillous histology. Another concern is that sessile serrated polyps (SSP’s) are particularly common in the proximal colon, are flat or sessile in shape, are difficult to detect a colonoscopy, and, other than hyperplastic polyps, and have a significant cancerous potential. However, there is also poor pathologist interobserver agreement in the differentiation of SSP’s from hyperplastic polyps (!!!)

— Colonoscopy has the clear advantages of high sensitivity for cancer and all classes of precancerous lesions, biopsy and diagnosis can be done right away, and there is a 10 year interval between examinations if all is normal. However, though the data are impressive through case-control studies as well as indirect trials (e.g. studies of fecal occult blood testing where large numbers of patients underwent colonoscopy), it is important to remember that there are no randomized trials of colonoscopy screening at this point. Disadvantages of colonoscopy include: thorough bowel prep (a pretty unpleasant procedure), higher risk of perforation than other modalities (0.5 per 1000), high risk of aspiration pneumonia with deep sedation, small risk of splenic injury, a greater risk of bleeding especially when biopsies are done (2.6 per 1000), and death (2.9 per 100,000). Also colonoscopy is operator-dependent, and they suggest that colonoscopists should have an adenoma detection rate greater than 25% (greater than 30% for males, greater than 20% for females), and cecal intubation rates should exceed 95%. and that patients ask/be aware of these numbers/ask the prospective colonoscopist

–FIT testing: noninvasive, one-time sensitivity for cancer 79%, about 30% sensitivity for advanced adenomas, low cost. Major disadvantage is need for repeated testing, poor or no sensitivity for serrated class precursor lesions (though there is no evidence that cancers arising from this class are less likely bleeds than those arising from adenomas). Given the requirement for annual testing, they suggest this is a more viable option in systems where there is programmatic screening available, and less dependent on clinicians remembering to offer annual screening. Although the sensitivity for FIT-DNA screening is higher (92% as well as 40% for SSP’s > 1 cm), they dismiss it because of substantial decrease in specificity and high cost

— flexible sigmoidoscopy: clearly reduce cancer incidence and or mortality in randomized trials. Lower cost and risk vs colonoscopy, more limited bowel preparation, no need for sedation. They also comment that the absence of sedation leads to low satisfaction experience for patients/less willingness to repeat the examination compared to colonoscopy (I wonder if this is really true). They do comment that there’s no reason to think that sigmoidoscopy needs to be at done at 5 year intervals as previously recommended, but that 10 year intervals are probably reasonable. And there are other blogs highlighting an observational study in UK finding decreased CRC incidence and mortality even after 17 years after a single sigmoidoscopy, as well as commenting on articles showing the benefits of colonoscopy for >15 years after a negative study)

— there are specific recommendations in other documents by MSTF regarding the technical performance of both FIT testing and sigmoidoscopy/colonoscopy, in order to achieve high quality results

— also, as they comment, “the best test is the one that gets done”. I think this reinforces the need to use a patient-centered approach to ordering these tests instead of just prescribing one

so,

— Some significant changes over prior recommendations, including placing the recommendations in tier groups instead of just listing them, elevating FIT testing to the top tier, and even suggesting that sigmoidoscopy could be done every 10 years

— I have sent out several blogs in the past suggesting sigmoidoscopy as a viable option to colonoscopy, even though it clearly misses more proximal lesions. Sigmoidoscopy has fallen out of favor for a variety of reasons in the United States, including, as noted in this recommendation, the poor reimbursement and therefore less availability of this modality. The data are mixed on the importance of finding right-sided lesions, with some studies showing minimal mortality benefit in finding and excising them (ie, the major argument against sigmoidoscopy that it does not see the right side may not matter that much).​ It would be useful to have an RCT with clear clinical outcomes assessing the relative values of sigmoidoscopy and colonoscopy.

— I must admit that I am quite impressed with the ease and acceptability for annual FIT testing, and the relatively low likelihood of requiring follow-up colonoscopy. However, I would certainly reiterate the MSTF concern about making sure there are systems to track this testing along with arranging for repeat testing. [As an aside, I should note that in Canada they recommend FIT testing every 2 years, and they actually discourage using colonoscopy for screening, given the higher cost, conscious sedation (and need a driver to take patients home), an awful bowel clean-out,  more risk,  and lack of data showing benefit over FIT testing].

Primary Care Corner: Racial disparities in interval colorectal cancer

11 Jul, 17 | by gmodest

A recent study looked at the racial/ethnic disparities in the development of interval colorectal cancer, defined as cancers that developed in a screened population but either were missed of the time of screening or developed de novo within the recommended screening/surveillance intervals (see DOI: 10.7326/M16-1154).

 

Details:

— a population-based cohort study of  Medicare enrollees aged 66-75 who had colonoscopy between 2002 and 2011, followed through 2013, with  linkage to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program

— total study population 61,433: 51,313 white/4196 black/2696 Asian/1164 Hispanic

— median age at index colonoscopy 70, 60% female (though higher in black and Hispanic persons), poverty level as defined by the ZIP Code of the patient’s residence was high in 32% white/69% black/36% Asian/67% Hispanic, urban 83% white/89% black/ 98% Asian/98% Hispanic, Charlson Comorbidity Index>= 2 in 2.5% white/6.5% black/3% Asian/6% Hispanic (reflects higher rate of comorbidities)

— similar screening colonoscopy rates between black and white persons (79.5% versus 80.7%), as well as similar polypectomy rates at the index colonoscopy (23.4% versus 24.7%)

— 2735 cases of interval colorectal cancer (CRC) were identified over 235,146 person-years of follow-up

— proximal 66% white/56% black/46% Asian/62% Hispanic

— rectum 18% white/25% black/35% Asian

— other data not provided because numbers too low/concerns about protecting patient confidentiality

— interval CRC was defined as a diagnosis 6-59 months after colonoscopy

— interval CRC, when found, was mostly within three years of prior screening: 66% white/71% black/72% Asian/65% Hispanic

— the study also evaluated whether any variation in incidence was related to the quality of the colonoscopy, as measured by the physicians’ polyp detection rate (PDR), with higher rate suggesting higher quality colonoscopy performed (a validated instrument)

 

Results:

— the probability of an interval CRC by the end of the follow-up was 7.1% in black persons and 5.8% in white persons, a 32% increase, HR 1.32 (1.15-1.51), after adjusting for age, sex, and year of colonoscopy (this ratio did not change with further adjustment by ZIP Code, comorbidity, or whether polypectomy was done at the index colonoscopy). The probability was lower in Hispanic (4.4%) and in Asian persons (3.8%)

— 52.8% of black persons versus 46.2% of white persons received colonoscopy from physicians who had a lower PDR. This PDR rate was significantly associated with interval CRC risk. Overall, the risk for an interval CRC was higher in patients whose colonoscopy was performed by physicians in the lowest quartile of PDR, with a dose-response curve

— However, adjustment for PDR did not alter the above HRs, decreasing the HR minimally from 1.32 to 1.31. Black persons still had a 35% increased interval cancer risk in those seeing physicians in the third-highest PDR quartile and 74% increase in those in the highest quartile. Also adjustment for colonoscopy by indication did not affect the results (see below).

— the disparity was more pronounced for cancer of the rectum, with a 70% increased risk [HR 1.70 (1.25-2.31)] and a 25% increase in the distal  colon [HR 1.45 (1.00-2.11)], but a nonsignificant difference in proximal cancer [HR 1.17 (0.96- 1.42)]

Black persons also had a significant 60% higher risk of distant disease associated with an interval CRC, but not for regional or local disease

 

Commentary:

— background: CRC is the third most common type of cancer in men and women, and the second leading cause of cancer-related deaths in the US. Interval CRC accounts for 3-8% of the CRC cases.

–There are important ethnic/racial disparities: black persons have the highest incidence of and mortality from CRC, 22 to 27% higher than white persons, as well as earlier mean age of CRC onset/higher % of cancers under age 50

— It is difficult to pinpoint the causes for these racial differences. Other studies have suggested that approximately 40% of the disparities in CRC incidence are from lower utilization of screening among black persons (though not found in this study). The above study looked at quality of screening, using PDR as a surrogate measure, and did find that black persons had more colonoscopies by physicians with lower PDR suggesting lower quality screening (though adjusting for this did not find any difference). This study did not look at other potential quality measures such as cecal intubation rates, colonoscopy withdrawal times, adequacy of bowel preparation, or completeness of polyp resection. In addition, there are no data about the characteristics/aggressiveness of cancers found, such as microsatellite instability. Also, as a large data-mining study, they do not have the actual specific indications for the colonoscopy itself though they did use patient characteristics and gastrointestinal conditions/symptoms within the prior 12 months to stratify screening versus non-screening. There was also no specific data about adenoma detection rate in the data, though other studies have suggested that PDR is well-correlated in other studies

— there may well be genetic differences in colon cancer predisposition among the groups, see blog  for a discussion of the interplay between nature and nurture

— it was notable that black persons had more interval cancers in the distal colon, though still more than half of the interval cancer lesions were still in the proximal colon in general. These distal lesions are easier to reach endoscopically and have fewer difficult to-detect sessile polyps, so are more effectively assessed/treated by colonoscopy. Estimates of 10 to 16% of proximal colon tumors are missed; and about 37% of interval rectal cancers are missed (? If there are racial/ethnic differences in these numbers). Though, the efficacy of detecting proximal lesions in preventing CRC deaths is much lower than distal lesions. However, despite the fact that distal lesions are easier to detect on colonoscopy, the important shift in pickup for black persons is the 60% higher incidence of distant disease in the interval cancers.

— another caveat is that black persons in this study were more likely to be poorer, urban, female and have more medical comorbidities, so there might well have been uncontrolled biases in the above observational study

— Asian persons have similar polyp detection rates as compared to white persons in prior studies. The lower incidence of interval cancers found in the current study is consistent with slower progression to cancer in this group.

 

So, the study does find a pretty dramatic increase in interval colon cancers in black persons. And, at the time of these diagnoses, the cancers were more aggressive and had more distant spread. It therefore does raise the question of whether there should be different criteria for colonoscopy screening based on race.

— for example, some guidelines suggest that black persons have colonoscopy beginning at an earlier age, with a recent suggestion of age 45 (this will be commented on further in an upcoming blog on new colorectal screening guidelines).

— the study also raises the question of whether there should be shorter surveillance intervals in black persons (and perhaps longer intervals in Asian patients). I would caution here that we do not have the important clinical outcome data to support this conclusion. And, the fact that these tumors often manifested themselves within three years, many already with distant spread in black persons, may suggest that increased screening would not be useful.

–so, we really need a large prospective RCT to assess the appropriate interval for CRC screening for different racial/ethnic groups, with granular data about the quality of the colonoscopy preparation, the adequacy of polyp resection, more specifics about the aggressiveness of polyps resected, etc., prior to submitting a large number of people do a pretty difficult, invasive and not-entirely-benign screening test, as well as potentially very aggressive treatment regimens depending on the outcome. There might also be a role of FIT testing versus colonoscopy in this group, or perhaps colonoscopy at the usual intervals but more annual FIT testing in between.

Primary Care Corner with Geoffrey Modest: antibiotics for skin abscesses?

10 Jul, 17 | by gmodest

by Dr Geoffrey Modest

A recent article found that either clindamycin or trimethoprim/sulfamethoxazole (TMP/SMX) are superior to placebo for uncomplicated skin abscesses (see Daum RS. N Engl J Med 2017;376:2545-55 ).

Details:

— multicenter, prospective, double-blind trial of 786 outpatient adults and children who had a skin abscess <5 cm in diameter (or <3 cm if 6-11 months old, <4 cm if 1-8 yo), and two of: erythema, swelling/induration, local warmth, purulent drainage, tenderness.

— patients randomized to clindamycin 150 mg TID vs TMP/SMX 80/400 mg BID vs placebo, for 10 days

— 57% male, mean age 25.5 (64% > 18yo/13% 9-17yo/21% 1-18yo/2% <1yo),  62% African-American/31% white, temperature 37°C, area of wound 4 cm², surrounding erythema 27 cm²

— all had incision and drainage of their abscess

— Exclusion criteria: infection in a body site requiring specialized management (perirectal, genital, hand infection), human or animal bites, oral temperature higher than 38.5°C (38.0°C in children 6-11 months of age), systemic inflammatory response syndrome, immunosuppressive therapy, immunocompromising conditions (e.g. diabetes, renal failure), BMI >40

Results:

— S. aureus was isolated from 527 (67%); MRSA was isolated from 388 (49%)

— intention-to-treat analysis 10 days after therapy: cure rate in clindamycin group was 83%, TMP/SMX group 82% (no statistical difference), but in the placebo group was 69%, significantly lower (p<0.001)

— For those who could be evaluated (those that completed the required study visits): 93% of clindamycin group, 93% of TMP/SMX group, and 81% of placebo were cured.

— children did slightly better than adults overall, especially in the clindamycin group

— For those without S. aureus, 90.5% on clindamycin, 90.8% on TMP/SMX , and 90.8% on placebo were cured (i.e. no benefit in non-S. aureus infections by antibiotics)

— for those with S. aureus (similar numbers for MRSA and MSSA), around 95% on clindamycin, 92% on TMP/SMX , and 70% on placebo were cured

— treatment failure was mostly because of a lesion at a different body site, or use of a rescue medication (done largely in the placebo group), but rarely due to worsening of the original lesion.

— at the one month follow-up visit:

–79% of the clindamycin group, 73% on TMP/SMX , and 63% on placebo remained cured.

–new infections at one month were less common in the clindamycin group (7%), than in the TMP/SMX group (14%), p=0.03, or the placebo group (13%), p=0.06

— adverse events were more common with clindamycin (22%) than with TMP/SMX (11%) or placebo (13%). All adverse events were without sequelae. One participant on TMP/SMX had a hypersensitivity reaction (fever, rash, thrombocytopenia, and hepatitis). Most common adverse events were diarrhea (16% clindamycin, 5% TMP/SMX, 7% placebo) and nausea (2%, 4%, 2%). No C difficile infections

Commentary:

— Skin abscesses are quite common, affecting 4% of people in the United States annually. Often these are treated as outpatients with clindamycin or TMP/SMX,  given the large percent of community MRSA

— In this study TMP/SMX was effective at a lower dose than often prescribed, though a 10-day course was given (vs 7 days). It is possible that the cure rates might have been higher with higher doses of TMP/SMX

— 13  patients had resistance to clindamycin and did not fare as well (54% cure vs 85% in clindamycin-susceptible infections). There were no cases of TMP/SMX resistance

— this study suggests that antibiotics help, though held-wisdom previously was that there was not much additional benefit after incision and drainage alone.

— there were minimal severe adverse reactions. Prior studies have found about 5% on TMP/SMX have severe reactions (and 1 person did above), and these can be fatal.

— for clindamycin, there was a meta-analysis (see Brown KA. Antimicrobial Agents and Chemotherapy 2013; 57: 2326) that found that, as compared to no antibiotic exposure, the Odds Ratio of C difficile infection for clindamycin was 16.80, fluoroquinolones 5.50, cephalosporins 5.68, macrolides 2.65, TMP/SMX 1.81

— it was mentioned in the supplementary materials of the current study that 33 in the placebo group (13%) used “rescue meds”, whereas 12 in clindamycin (5%) and 15 in TMP/SMX (6%)​ did. There is no comment on what meds were used or what the outcomes were for those who continued with their assigned meds/placebo and did not require rescue meds

so:

–it seems quite likely from this study that antibiotics help, as also noted in a prior blog , a study comparing TMP/SMX at 4-fold higher doses (320/1600 mg bid) finding benefit from the antibiotic but noting that >80% responded just to I&D.  And, 80+% of people seem to get better without antibiotics (in several other studies), and even in this study, 81% of those completing the study were cured. (70% of those with documented S aureus infections).

— there are really bad/occasionally lethal short-term potential adverse events from these antibiotics, especially severe systemic reactions to TMP/SMX and severe C difficile infections with clindamycin

–and there are potential long-term bad effects on the microbiome. As an example, this blog reviews a large prospective observational study finding antibiotic usage was associated with later development of colonic adenomas, including high-risk ones

–it was also notable in this study that there were not many cases of the abscess area getting worse in the placebo group with “treatment failure”

–so, in lower risk patients (nondiabetics, immunocompromise, etc), it might be reasonable just to watch the patient, holding the antibiotics but prescribing them if they were not getting better in a few days. I would be inclined to use antibiotics even in this lower-risk group if there were uncertainty about being able to have close followup (returning to clinic or phone followup), to assess the progress.

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

 

EDITORIAL BOARD members will have the opportunity to:

  • Author commentaries on the latest research that matters;
  • Contribute to series articles that offer relevant EBM insight;
  • Contribute to blog articles on the dedicated BMJ EBM site
  • Receive reduced rates to EvidenceLive and upcoming events
  • Receive regular evidence updates.
  • Contribute to peer review;
  • Receive online journal access,
  • Open access submission fees;

 

If you want to become a flagbearer for the EBM community then we’d very much like to hear from you. To apply please fill out the form here: bmj.co/EBM_BM

 

Professor Carl Heneghan

Editor in Chief, BMJ Evidence-Based Medicine

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.

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