Articles from the Past Year Or So That May Change Your Practice

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Articles from the Past Year Or So that May Change Your Practice

Mark Graber, MD FACEP
Professor
Christopher Hogrefe, MD
Assistant Professor

Departments of Family and Emergency Medicine
University of Iowa Carver College of Medicine

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Sacred Cows

Image: A photograph shows a cow standing on a city street.

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Image: A collaged photo shows a cow lying with its feet in the air as if dead; the Spanish Inquisition from Monty Python looks on in horror and exclaims "Egad! Not another one?"

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Quassem et al. Appropriate Use of Screening and Diagnostic Tests to Foster High-Value, Cost-Conscious Care. Ann Intern Med 2012;156:147-149.

How can we reduce health care costs by using only high value screening and diagnostic tests?

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• Delphi technique in which "experts" come to a consensus on each item.

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BOGSAT

Image: A photograph shows a group of Victorian gentlemen.

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GOBSAT

Image: A photograph shows two men on a boat.

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What did they decide are money wasters? 37 tests...

• Cath in patients with stable angina.
• "Routine" EKG.
• PAP smear for those >65 years of age or those who have had a hysterectomy for benign disease.
• Colon cancer screening in those >75 years of age.
• Almost any routine pre-operative testing.
• Sinus imaging.
• D-dimer in those who are not low risk.
• Imaging in those with syncope and normal neuro exam.
• Imaging studies in those with non-specific low back pain.

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And, in fact

• Back Pain: https://archive.ahrq.gov/research/jan03/0103RA9.htm.
• Cath in stable angina: Arch Intern Med 2012;172(4):312-319.
• D-dimer: Newman, D.H., et al, Ann Emerg Med 57(6):622, June 2011.

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Schjerning Olsen A-M et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study. Circulation 2011 May 24; 123:2226. C

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Even short term NSAIDS [nonsteroidal anti-inflammatory drugs] lead in increased Cardiovascular Risk

• >83,000 Danish Registry.
• Mean age 68, 63% men.
• Looked at hospitalization after FIRST MI [myocardial infarction] in relationship to NSAIDS.
• So... these patients had known CAD [coronary artery disease].
• 42% received an NSAID.
• 42% of the whole cohort had death or recurrent MI.

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• Hazard Ratio for MI in 1st week of NSAID use: 1.45 (45% increase)
• Hazard Ratio going forward >90 days: 1.55 (55% increase)
• All NSAIDS except Naproxen (statistical fluke??) → Naproxen does seem to be the drug of choice, though.

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Bangalore S et al. Angiotensin receptor blockers and risk of myocardial infarction: Meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ 2011 Apr 26; 342:d2234. (http://dx.doi.org/10.1136/bmj.d2234)

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Image: A photograph shows a bucket full of money being poured into a toilet.

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We know not all BP [blood pressure] lowering is equal.

ALLHAT, Beta-blockers, alpha-blockers

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What we know

• ARBS [angiotensin receptor blockers] don't decrease mortality in those with diabetic nephropathy. BMJ 2004 Oct 9; 329:828-31.
• Some hint ARBS worsen cardiovascular outcomes.
• "The ARBS-MI Paradox."

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This Study

• Well done meta-analysis of 37 trials (with 39 arms) of ARBs vs Placebo or active drug for HTN [hypertension].
• 147,000 patients total. 3.3 year follow-up.
• Sensitivity analysis: highest bias and and lowest bias studies came to same conclusion.
• Good homogeneity of studies.

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• What did they find?
  • Lower risk of stroke (RR reduction 10%).
  • Lower heart failure (RR reduction 13%).
  • Lower risk of diabetes (RR reduction 15%).
• But wait for it...

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Image: The figure compares outcomes for angiotension receptor blockers (ARBs) and myocardial infarction, stratified by comparison group (placebo versus active treatment).

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Image: The figure compares outcomes for ARBs and cardiovascular mortality, stratified by comparison group (placebo versus active treatment).

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Image: The figure compares outcomes for ARBs and all cause mortality, stratified by comparison group).

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But wait for it...

• BMJ editors say, based on the data:
  • "Despite lower blood pressure with angiotensin receptor blockers when compared with placebo, there also was no detectable beneficial effect for the outcome of myocardial infarction or cardiovascular mortality."
• No benefit in overall mortality.
• QED. Use something else.

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Well done meta-analysis

• Did not get unpublished data but this would likely have supported their conclusion (un-spinable studies critical of ARBs likely would not see the light of day).
• Good homogeneity.

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• Do nothing which is of no use.
  • Miyamoto Musashi.

Image: A Japanese print shows a Samurai warrior.

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Howard R, et al. Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease. N Engl J Med 2012;366:893.

Does memantine add anything to donepezil for moderate to severe Alzheimer's disease?

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Previous Literature

• NNT 12.
• No important positive outcomes (time to nursing home, ability to do ADLs [activities of daily living], etc.).
• Donepezil not effective in minimal cognitive impairment.

• Cholinesterase inhibitors for patients with Alzheimer;s disease: systematic review of randomized trials, BMJ 2005;331;321-327.
• Doody RS et al. Donepezil treatment of patients with MCI: A 48-week randomized, placebo-controlled trial. Neurology 2009 May 5; 72:1555.

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• 285 Patients randomized.
• Double-blind, randomized, 2x2 factorial design study of donepezil +/- memantine vs placebo for moderate-to-severe community-dwelling patients with probable Alzheimer dementia.
• Outcome: Mini mental status exam: 0-30.
• Bristol ADL Scale: 0-60.

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Outcome

• MMSE: Memantine + donezapil vs. placebo + donezapil: 1.2.
• BALDS: Memantine + donezapil vs. placebo + donepazil: 1.5 points.
• MMSE: donepazil vs. placebo: 1.9 points.
• BALDS: donepazil vs placebo: 3.0 points.

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• Their conclusions:
  • Memantine adds nothing to donepazil—I'll buy that.
  • Donepazil has "significant functional benefit" over placebo—Not so fast.

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Hmmm...

• They decided arbitrarily that clinically "significant" was 1.4 on the MMSE and 3.5 points on BALDS based on:
  • ...0.4 SD from baseline....
  • The response seen from 127 patients.
• Nowhere does this say anything about clinically detectable differences.

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Bristol Activity of Daily Living Scale: BADLS: 0-60

Images: Two line graphs compare memantine and donepezil (placebo versus active treatment).

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No difference between donepazil + memantine vs. donepazil alone.

• What do we take from this?
  • The combination of donepezil and memantine for moderate-to-severe AD is not beneficial.
  • The discontinuation rates of dementia medications are high.
  • The "clinically significant" benefit is marginal.
  • If you start donepezil (or another AChE inhibitor) for dementia, it's reasonable to continue it through the course of the disease (or not... you could argue either point with this article).

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Zeiger RS et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med 2011 Nov 24; 365:1990 c.

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What we know...

• Oral steroids for acute exacerbations often cause behavioural problems in children.
• 1mg/kg/d is as good as 2mg/kg/d.
• Chest 2002;122;624-628 DOI 10.1378/chest.122.2.624.

• Treating those that wheeze with URIs [upper respiratory infections] at the start of the URI is helpful

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This article...

• Compared 278 children age 12-53 months randomized to:
  • Low dose budesonide daily (0.5mg BID).
  • High dose budesonide 1mg BID for 7 days at onset of wheezing or URI symptoms.
• These were all children who had required oral glucocorticoid therapy, ED visit (??), hospitalization.

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Outcome

• No difference in need for oral glucocorticoids.
• No difference in time to first exacerbation.
• No difference in growth, etc.
• No difference in treatment failure.
• 104 mg less budesonide in intermittent group.

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So what do I take from this?

• Am I ready to stop controlled meds on my asthma patients? NO.
• But for those who we only burst with steroids for a URI this is an acceptable option.

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Calcium and Bisphosphonates are killing me...

Image: An 18th-century woodcut shows dead bodies being gathered into a cart in a city street.

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Park-Wyllie LY et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 2011 Feb 23; 305:783.

And

Schilcher J et al. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011 May 5; 364:1728.

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What we know...

• Bisphosphonates reduce bone remodeling.

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First study

• Population based, nested, case control study.
• 716 women over age 68 who were taking a bisphosphonate and had an atypical hip fracture over 7 years.
• 3580 controls on bisphosphonates but with no fracture.

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• "Long term" versus transient bisphosphonate use associated with "atypical" hip fracture OR of 2.74 for fracture.
• 2 of 1000 women so absolute risk is low.
• Still reduced "typical" hip fractures that were much more common.

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Next study

• Sweden. Looked all all hip fractures in 2008.
• Total of 1271 fractures.
• Of these, 59 were "atypical."
• Relative Risk for atypical fracture with bisphosphonate use was 47.3.
• But... still only 5 more per 10,000 patient-years.

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• 78% of "atypical" fractures had used bisphosphonates.
• 10% of controls had used bisphosphonates.
• Likelihood went up with duration of bisphosphonate use.

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Should we have a drug holiday at 5 years?

In whom should we continue the drug?

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Finally some guide: opinion only, though.

N Engl J Med 2012; 366:2048-2051. May 31, 2012.

N Engl J Med 2012; 366:2051-2053. May 31, 2012.

• Patients with low bone-mineral density at the femoral neck (T score below -2.5) following 3 to 5 years' of treatment have the highest risk for vertebral fracture and seem to benefit most from treatment continuation.

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• Those with existing vertebral fractures who have T scores below -2.0 may also benefit.
• Those with femoral neck T scores above -2.0 have low vertebral fracture risk and are not likely to benefit.

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OK. We solved that problem. What about calcium?

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Li K, Kaaks R, et al. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 2012;98:920-925.

So what about this calcium and heart attack thing anyway?

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• 25,540 local residents, who were then aged 35-64 years.
• Free of CVD [cardiovascular disease] at baseline.
  • Excluded participants with: MI, stroke, or transient ischaemic attack (but not angina, etc.).
• Used a validated food frequency questionnaire.

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For calcium supplements...

• Cardiovascular events diagnosed by:
  • Patient report.
  • Family report (if dead).
  • Verified by death records or medical records.
• MI, stroke, overall CVD.
• Recent calcium use defined as in past 4 weeks, where 'regularly' was defined as daily use for at least 1 week or non-daily use of at least five doses on a regular basis.

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• Logistic regression to adjust for confounders.
• Ran 4 different models.
• 11 year follow-up.

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• 354 MI and 260 stroke cases and 267 CVD deaths.
• Users of calcium supplements and MI:
  • HR 1.86 (95% CI 1.17 to 2.96).
  • Calcium supplement only users HR 2.39 (95% CI 1.12-to 5.12).

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But...

• "Most recent but not the cumulative calcium only supplementation was significantly positively associated with MI risk (HR=2.17; 95% CI 1.06 to 4.42)."
• They also didn't collect data on cumulative dose (only frequency).

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Huh?

• Recent but not cumulative calcium supplement dose associated with CAD (??!)
  • This would seem to undermine the proposed mechanism of increased plaque formation.
• No change in stroke risk or overall CVD mortality.
• Of course, reported as 86% increase in MI.
• Absolute risk very low.
  • Out of 25,000+ participants: 354 MI and 260 stroke cases and 267 CVD deaths.

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Image: A detail from a table taken from a journal article compares myocardial infarction rates by various calcium supplements and other supplements.

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Warensjo E et al. Dietary calcium intake and risk of fracture and osteoporosis prospective longitudinal cohort study. BMJ 2011; 342:d1473 doi: 10.1136/bmj.d1473 (Published 24 May 2011).

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Second study

• Cohort study of 61,433 women born 1914-1948.
• Study started 1987 and was of fracture risk.
• Based on the Swedish Mammography Cohort.
• 5022 in the sub-cohort that looked at Dexa scans.
• Followed for 19 years.
• Calcium intake as reported by patients.

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• Calcium intake of 750mg-882mg/day (second quintile) was as good at preventing fractures and osteoporosis as were higher levels of calcium intake.
• In fact, highest quintile had Hazard ratio = 1.19 (95%CI 1.06-1.32) for hip Fx.

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Heart June 2012 Vol 98 No 12

• Calcium monotherapy: Treating 1000 older adults with calcium SUPPLEMENTS for 5 years:
  • 14 more heart attacks.
  • 10 more strokes.
  • 13 more deaths.
  • 26 fewer fractures.
• Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:C3691.

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Luckily, AHRQ and USPSTF [U.S. Preventive Services Task Force] to the rescue...

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www.uspreventiveservicestaskforce.org/draftrec3.htm

• The USPSTF recommends against:
  • Daily supplementation with ≤400 IU of vitamin D3 +1,000 mg of calcium carbonate. For the primary prevention of fractures in non-institutionalized postmenopausal women.
• Insufficient evidence for higher dose Vit D.
  • Draft recommendation AHRQ Publication No. 12-05163-EF-2.

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Search for the holy grail of treating back pain.

Images: Dante Gabriel Rossetti's painting, "The Holy Grail," a page from a medieval book showing an illustration of knights seeking the Grail, and a photograph of a jeweled chalice are shown.

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Hot Off The Presses...

Radcliff K, et al. The impact of epidural steroid injections on the outcomes of patients treated for lumbar disc herniation: a subgroup analysis of the SPORT Trial. Journal of Bone and Joint Surgery 2012 August 1; 94 (15): pgs. 1353-1358.

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The Nitty Gritty

• A subgroup analysis of a prospective, multicenter study of operative versus non-operative treatment of lumbar interverterbral disc herniation.
• 154 patients who received epidural steroid injections during the SPORT trial (with no previous injections) vs. 453 patients who never received an injection (before or during the SPORT trial).

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Gauging Success (or Failure)

• Compared both primary and secondary outcomes at four years and the rates of surgical/non-surgical treatments.
  • Primary outcomes = bodily pain, physical function, and physical/mental component summary.
  • Secondary outcomes = self-reported improvement, work status, and satisfaction.

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The Bottom Line

• Patients with lumbar disc herniation treated with epidural steroid injections had no improvement in short and/or long-term outcomes.
• However, there was an increased prevalence of crossover to non-surgical treatment.
  • Confounded by a preference for surgical avoidance.

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Other references of randomized studies that come to the same conclusion

• Cohen SP et al. Epidural steroids, etanercept, or saline in subacute sciatica: A multicenter, randomized trial. Ann Intern Med 2012 Apr 17; 156:551. (http://www.annals.org/content/156/8/551.full)
• Cohen SP. Epidural steroid injections for low back pain. BMJ 2011 Sep 13; 343:d5310. (http://dx.doi.org/10.1136/bmj.d5310)

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And Thus...

What is a provider to do?

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Stergiopoulos K and Brown DL., Initial Coronary Stent Implantation With Medical Therapy vs Medical Therapy Alone for Stable Coronary Artery Disease. Arch Intern Med 2012 Feb 27; 172:312.

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Sisyphus trying to get physicians to act rationally.

Images: Two paintings of Sisyphus pushing a rock up a steep hill are shown.

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What we know

• COURAGE trial supported by AHRQ showed no benefit to stenting versus optimal medical management. N Engl J Med 2007; 356:1503-1516 April 12, 2007.
• We also know that this hasn't changed practices. Borden WB et al. JAMA 2011 May 11; 305:1882.

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Why another meta-analysis

• Prior meta-analyses included patients who had simple balloon angioplasty and who did not have the current standard of care for optimum medical therapy.

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This study

• 8 trials with 7229 patients using patient level data.
• 3 studies stable patients after MI.
• 5 studies stable angina with some sort of provocative test.
• Follow-up was 4.3 years.

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Images: Five tables compare initial stent implantation versus medical management for 5 outcomes: Death, death with 0.5 added to cells with no mortality events reported, nonfatal myocardial infarction, unplanned revascularization, and persistent angina during follow-up. All included studies are shown by name along with point estimates of the odds ration and respective 95% CIs.

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Results in numbers:

• Death (all cause): 8.9% vs. 9.1% (OR 0.98 95% CI 0.84-1.16).
• Non-fatal MI: 8.9% vs. 8.1% (OR1.12 95% CI .93-1.34).
• Unplanned revasc: 21.4% and 30.7% (OR, 0.78; 95% CI, 0.57-1.06 favoring stent.
• Persistent angina, 29% and 33% (OR, 0.80; 95% CI, 0.60-1.05).

Slide 77

Diabetes

Slide 78

More confusion...

Image: M. C. Escher's drawing "Convex and Concave" shows a building made up of stairs, arches, and bridges using tricks of perspective and inversion that make it appear that objects are both inside and outside and occasionally upside down.

Slide 79

Editorial: ARCH INTERN MED VOL 172 (NO. 4), 320 FEB 27, 2012

• Reducing even 1/3 of the caths would save $6 billion to $8 billion annually.
• "While physicians outwardly worship at the altar of evidence-based medicine, in reality, we more often tend to practice selective evidence-based medicine by adopting and embracing those trials and studies with results that reinforce our existing clinical practice preferences or biases...."

Slide 80

Farmer AJ et al. Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes. BMJ 2012 Feb 27; 344:e486.

The issue: does home glucose monitoring help to improve overall glucose control?

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• The study: 6 randomized trials with >2,500 participants.
• A "useful" intervention should decrease HbA1c by at least 0.5%.

Slide 82

Home glucose monitoring

• The answer: "yes with a but..."
  • Mean A1c levels were 8.3% at baseline.
  • Patients in the self-monitored groups showed the following statistically significant differences from the non-monitored groups.
  • No difference at all if A1c >10%.

Slide 83

Home glucose monitoring

• What do we take from this?
  • Home glucose monitoring does little to improve overall glucose control in those not taking insulin.
  • Home glucose monitoring is necessary for patients on insulin or who have hypoglycemic episodes (or at least we don't have data to say otherwise...).

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What else do we already know...

• Tight blood pressure control does not make any difference in those with pre-exisitng disease.

• The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010 Mar 14; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1001286).
• JAMA 2010;304(1):61-68. doi: 10.1001/jama.2010.884.

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How about tight glucose control?

ACCORD study group. Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes. N Engl J Med 2011;364:818-28.

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• 77 clinical sites.
• Age 40-79, DM [diabetes mellitus] type II, A1c 7.5% or >.
• Randomly assigned to intensive control:
  • HbA1c goal 6%.
  • HbA1c goal 7%-7.9%.
• Approx 5000 in each group.

Slide 87

• Terminated intensive control arm early (3.7 years).
  • Maybe longer follow-up would change outcome → adverse events may cluster as years progress??
• Non-fatal MI lower in intensive group (1.08% vs. 1.35%, HR 0.79 (95% CI 0.66-0.95) at time of transition.
• Fatal Cardiovascular disease higher (not statistically significant early on but...).
  • By end of study was statistically significant.

Slide 88

• 21% higher all-cause mortality HR 1.42 vs. 1.16 (95% CI 1.02-1.44)
• Not the cleanest study: included interventions for BP, triglycerides, lipids.
• No interaction between these and primary outcome except...
• Intensive glucose control + intensive BP control = worse outcomes.

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This shouldn't be surprising.

Large British study of tight control showed only difference was in retinopathy and then only with metformin.

Slide 90

Tight control may not change renal outcomes.

Arch Intern Med 2012;172(10):761-769. doi:10.1001/archinternmed.2011.2230.

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Amazingly, the ADA agrees.

Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Published online before print, April 19, 2012, doi: 10.2337/dc12-0413. Diabetes Care April 19, 2012. http://care.diabetesjournals.org/content/early/2012/04/17/dc12-0413.full.pdf+html

• Up to HbA1c of 8% is OK and maybe 8.5%.

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Approach to management of hyperglycemia:

Image: A chart shows the approach to management of hyperglycemia. Each condition listed below is accompanied by an elongated colored triangle labeled "More Stringent" at the narrow end and "Less Stringent " at the broad end with recommendations for approach at each end:

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Implications for quality measures?

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Kavousi M et al. Evaluation of newer risk markers for coronary heart disease risk classification: A cohort study. Ann Intern Med 2012 Mar 20; 156:438. (http://www.annals.org/content/156/6/438.full)

Do any of the new risk markers (such as CRP) add anything to the prediction of CAD risk?

Slide 95

• Data that were collected prospectively from the Rotterdam Study of almost 6000 asymptomatic community-dwelling participants (mean age, 69) without known CHD [coronary heart disease].

Slide 96

Looked at the following:

• Prohormone brain-type natriuretic peptide (NT-proBNP).
• von Willebrand factor antigen.
• Fibrinogen.
• C-reactive protein (CRP).
• Pulse wave velocity.
• Homocysteine.
• Uric acid.
• Glomerular filtration rate.
• Leukocyte count.
• Coronary artery calcium score (CAC).
• Carotid intima—media thickness.
• Presence of peripheral artery disease.

Slide 97

Weakness

• Only half of the participants were evaluated for CAC and CRP.

Slide 98

Controlled for Framingham Risk Score

• Only two markers increased the hazard ratio by 2 or more.
• NT-proBNP: HR: 2.5.
• Coronary artery calcium score: HR 6.2.
• So now that we can predict, what can we do to prevent?

Slide 99

News about statins

• The Food and Drug Administration (FDA) has changed some if its recommendations and warnings about HMG-CoA-reductase inhibitors ("statins").
• http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

Slide 100

News about statins

• Liver enzymes every year?
  • Nah...
  • Routine periodic testing of liver enzymes is neither necessary for safe statin use nor effective for identifying rare liver toxicity early.
  • New recommendation, to quote the FDA: "before starting statin therapy and as clinically indicated thereafter."

Slide 101

News about statins

• What about memory and blood sugar concerns?
• FDA states that non-serious and reversible cognitive changes have been associated with statin use (AERS data).
  • Observational and prospective studies have not found this association (*).
• FDA states that elevations in glucose and A1c levels have been associated with statin use.
  • Relative risk of new onset DM in patients on statins ranges from 9 – 13% and appears real (+).

Slide 102

• What do we learn from this?
  • Skip the "annual ALT" for statin monitoring. It just leads to more incidental findings of abnormal LFT's.
  • Watch for the development of DM in those at risk patients on statins. However, the small increased risk of DM does not outweigh the benefits of appropriate statin use.
  • Cognitive changes are highly subjective and potentially due to myriad causes. Use this warning with caution.

Slide 103

Po Lai Yau et al Impairments in Adolescence.Obesity and Metabolic Syndrome and Functional and Structural Brain. September 3, 2012.
http://pediatrics.aappublications.org/content/early/2012/08/28/peds.2012-0324

Slide 104

What we already know:

• Metabolic syndrome is associated with neurocognitive imparements in adults.
• Metabolic syndrome is being seen with increasing frequency in children.
• This has not been looked at in children (until now).

Gatto NM, et al. Metabolic syndrome and cognitive function in healthy middle-aged and older adults without diabetes. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2008;15(5): 627—641.

Slide 105

The group

• Defined metabolic syndrome as:
  • Increased insulin levels.
  • ATP III definition of HTN and obesity.
  • National Health and Nutrition Examination Survey (NHANES) for triglycerides.
  • Stringent adult levels for HDL.
• Need 3/5 to define adolescent Met Syn.

Slide 106

• Age 14-20.
• Exclusion criteria:
  • DM2.
  • Any significant medical problems.
  • Tanner stage <4.
  • Depression or use of psychoactive drugs.
  • Hx learning disability.
  • Pregnancy.
  • MRI abnormality.

Slide 107

• Screened 129:
  • 18 excluded (DM, did not meet criteria, 6 failed to complete screening).
• 49 with met syn.
• 62 without met syn.

Slide 108

• Standardized tests:
  • Tested IQ, academic achievement, memory skills and executive functioning, ability to pay attention.
  • MRI (I don't pretend to understand this methodology).

Slide 109

Results

• Both groups balanced in socioeconomic status, ethnicity, gender.
• Cohen Effect Size.
• 0.2 to 0.3: Small.
• 0.5: Medium.
• 0.8 and greater: large.

Slide 110

Image: A detail from a table compares cognitive data by measures.

Slide 111

Problems

• Didn't do Bonferroni correction.
• Small sample size (may actually be bigger differences based on effect sizes).
• Association does not equal causality.
  • Is it reversible? Is it cause and effect or does decreased intellect cause overeating and Met Syn?
• Very small absolute differences: is it important?

Slide 112

Good stuff

• "Dose response effect": Level of functioning decreased with increasing number of Met Syn criteria.
• Same found in DM2 in adolescents but more pronounced.

Slide 113

Jha AK et al. The long-term effect of premier pay for performance on patient outcomes. N Engl J Med 2012 Mar 28; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMsa1112351).

Does "improvement" in process translate into improvement in patient outcomes?

Slide 114

• Medicare data for 250 hospitals participating in Medicare's Premier Hospital Quality Incentive Demonstration.
• 3300 hospitals that participated in public reporting alone (non-Premier).
• Used Medicare part data 2002-2009.

Slide 115

6 million patients

• Two diagnoses linked to incentives:
  • Acute myocardial infarction.
  • Coronary-artery bypass grafting.
• Two diagnoses not linked to incentives:
  • Congestive heart failure.
  • Pneumonia or who underwent.

Slide 116

• Outcome was death.
• Did multivariate analysis to control for confounders: 5 models.
• Looked at staffing rates, rural vs urban, ownership, financial margins, etc.
• Adjusted risk of death for 29 conditions.

Slide 117

Results

• No difference in mortality between participating and non-participating hospitals.
• Baseline: 12.33% vs. 12.40% (95% CI -0.4, 0.26).
• Outcome: 11.82% vs. 11.74% (95% CI -0.30-0.46).

Slide 118

• Improvement in mortality at the same rate.
• How about CABG?
  • Higher mortality at premier hospitals.
  • 4.12% vs. 3.34% (95% CI 0.2%-1.36%).

Slide 119

Image: A table shows mortality at 30 days for study conditions at participating hospitals. Mortality data for all conditions, acute myocardial infarction, congestive heart failure, pneumonia, and coronary artery bypass grafting are compared.

Slide 120

We know guidelines work. What is the problem here?

Image: An empty suit, with a question mark where a man's head ought to be, stands in front of the World Health Organization logo.

Slide 121

Heterogenous patients/hospitals. Maybe wrong quality measures.

Slide 122

Image: A table compares hospital and patient characteristics for premier and non-premier hospitals.

Slide 123

Image: A detail from a table shows percentage of coexisting conditions: diabetes, hypertension, chronic kidney disease, and chronic pulmonary disease.

Slide 124

But it does make the point that simple pay for performance likely doesn't work well.

Slide 125

J Emerg Med 2011 Mar;40(3):262-6.
Post Concussion syndrome is common.

And sticks around for a while.

Slide 126

Postconcussion syndrome

• Concussion does not equal LOC.
• Concussion = any neurologic dysfunction after head injury..
• 94 patients in two Canadian EDS..
• Inclusion criteria:
  • Any sx.
  • GCS =15.

Slide 127

• Not necessarily your ordinary patient with minor head trauma.
  • Were allowed hospitalization and <20 minutes LOC.
• BUT...
  • Only 17% had CT scans.
  • All were discharged from the ED.
• So, were essentially the people we see.

Slide 128

Used a validated scale

• 68/94 concussive symptoms at baseline.
• 59/94 (63%) still had sx at one month.

Slide 129

Image: Details from a table shows number of cases of types of concussive symptoms.

Slide 130

What is (unfortunately) "new" in Breast Cancer Treatment?

Jeevan R. et al. Reoperation rates after breast conserving surgery for breast cancer among women in England: retrospective study of hospital episode statistics BMJ 2012;345:e4505 doi: 10.1136/bmj.e4505

and

McCahill LE et al. Variability in reexcision following breast conservation surgery. JAMA 2012 Feb 1; 307:467.

Slide 131

Question: What percentage of patients with breast conserving therapy need a second operation?

What percent need it and don't get it?

Slide 132

The JAMA article

• 2206 women with invasive breast cancer who underwent open biopsy or partial breast conserving therapy.
• 23% needed a second surgery on the same breast (bad).
• 311 with positive margins did not undergo a second procedure (14%).

Slide 133

• Total mastectomy on second surgery about 1/2: 9%.
• Limited to 4 institutions...
• BMJ article: 55,297 women:
  • All adult women in Britain undergoing breast conserving mastectomy from April 2005-March 2008.

Slide 134

• 11,032 (20.0%, 95% CI: 19.6% to 20.3%) had second surgery.
• Interestingly:
  • Carcinoma-in-situ: 30% (adjusted odds ratio 1.9, 95% CI 1.8 to 2.0).
  • Locally invasive disease: 18%.
• 11% breast conserving, 7% total mastectomy.

Slide 135

What are the implications for informed consent?

What are the implications for quality measures?

Slide 136

Saving money by treatment at home.

First, new chest guidelines.

Slide 137

You can use the cheap stuff without monitoring

• "For outpatients with VTE treated with SC UFH, we suggest weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weight-adjusted dosing with monitoring."
• Chest 2012;141:7S-47S.

Slide 138

But is it safe?

Aujesky D et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: An international, open-label, randomised, non-inferiority trial. Lancet 2011 Jul 2; 378:41.

And

J Thromb Haemost 2011 Aug;9(8):1500-7. doi: 10.1111/j.1538-7836.2011.04388.x.

Slide 139

• 19 Eds.
• 171 outpatients.
• 168 inpatients.
• Open label, randomized, non-inferiority.
• Patients had to have a risk of dying of less than 4% based on the PE Severity Index.

Slide 140

Exclusion criteria

• O2 sat <90%.
• BP <100 systolic.
• Chest pain requiring opioids.
• High risk of hemorrhage (recent stroke, bleed, etc.).
• Platelets <75,000.
• Cancer only 1% outpatients.
• Cancer only 2% inpatients.

Slide 141

Image: The Pulmonary Embolism Severity Index card is shown.

Slide 142

• All got enoxaparin 1mg/kg SQ followed by warfarin at least 90 days.
• 1 person in each group died. Neither from PE.
• 1 person in outpatient group had recurrent disease.
• Bleeding in 3 outpatients (IM hematoma day 3 and day 13 and menorrhagia day 50) → at day 13 and 50 not likely to be due to treatment.

Slide 143

It does make the point that outpatient treatment is safe... And there is this....

Büller HR et al. for the EINSTEIN—PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012 Mar 26

Slide 144

Actually well done study.

• Randomized 4833 to rivaroxaban or enoxaparin+ warfarin.
• Randomized to 3, 6, or 12 months of drug.
• Actually were very good about calling death from PE.

Slide 145

Image: A table compares clinical outcomes for Rivaroxabin versus Standard Therapy.

Slide 146

Not FDA approved for this application.

But look for it soon.

Slide 147

Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011 Oct 4; 124:1573.

Slide 148

What we know...

• Both rivaroxaban and dabigatran are now approved for use in atrial fibrillation.
• Dabigatran is a direct thrombin inhibitor.
• Rivaroxaban is a Factor Xa inhibitor.
• The downside is it has been "impossible" to reverse them.

Slide 149

This study

• Hypothesis: Prothrombin concentrates may reverse direct thrombin inhibitors and factor Xa inhibitors because they have a high concentration of factors II, VII, IX and X.

Slide 150

• 12 healthy volunteers.
• Double blind crossover study.
• Treated with either drug for 2.5 days.
• Hospitalized for Prothrombin complex concentrates IV.
• On a battery of tests there was reversal with rivaroxaban but not dabigatran.
• Dabigatran is dialyzable (60%).

Slide 151

So what is the problem...

1. Healthy patients.
2. Did show effect on reversing bleeding...lab tests surrogate markers only.
3. Not exactly chronic use of the drugs.

Slide 152

Monitoring??

• Dabigatran: apTT>2.5 normal = over anticoagulation (??).
• Shoot for 1.5-2 X normal.
• Rivaroxaban:
  • Factor Xa levels.
  • Elevated PT associated with drug concentrations.

Slide 153

Turns out you can monitor dabigitran...for a price

Guess who sells the kit used for monitoring??

Slide 154

Ecarin Clotting Time (ECT)

• Monitoring for dabigatran.
• Not effected by other anticoagulants.
• Thrombin Time:
  • Also used for monitoring direct thrombin inhibitors.
  • Sensitive to other anticoagulants, though.

Slide 155

Image: An autographed photo of Frank Gorshin as the Riddler is shown.

Slide 156

Bonus Topics

Slide 157

Shingles

Tseng HF et al. Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease. JAMA 2011;305:160.

Slide 158

Image: A line graph shows the percentage of Herpes Zoster incidents for the vaccinated and unvaccinated through 3 years of follow-up. The vaccinated percentage rises to 2%; the unvaccinated rises to nearly 4%.

Slide 159

• Large retrospective cohort study of older adults.
• 55% fewer cases of zoster in the vaccine group (6.4 cases per 1,000 person-yrs vs 13 cases per 1,000 person years).
• 65% fewer hospitalizations and 63% fewer cases of ophthalmic zoster.

Slide 160

Shingles

• What do we take from this?
  • In the 'real world' the zoster vaccine works about as well as it did in the initial studies.
  • We can be confident in recommending the zoster vaccine for its efficacy (but cost is another matter...).

Slide 161

Not another infectious disease guideline!

Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months
SUBCOMMITTEE ON QUALITY IMPROVEMENT AND STEERING MANAGEMENT SUBCOMMITTEE ON URINARY TRACT INFECTION and STEERING
Pediatrics; originally published online August 28, 2011;DOI: 10.1542/peds.2011-1330

Slide 162

What we know?

• Treatment and diagnosis is all over the place.
• Workup after 1st episode?
• Workup after 2nd episode?
• And what workup should be done.

Slide 163

Some answers

• Analysis of medical literature.
• UTI defined as pyuria and at least 50,000 cfu.

Slide 164

What do they recommend?

• US for all children after first febrile UTI (Level of evidence: C).
• No VCUG [voiding cystourethrogram] unless US shows scarring of kidneys, hydronephrosis, etc. (Level of evidence: B).
• Modelling: Only 1:100 will have grade V.
• No prophylactic antibiotics if grade I-IV reflux (Level of evidence: ??? But RCT).

Slide 165

Preventing Obesity in Children

• Crossing growth percentiles.
• Avoid Prolonged Bottle use.
• Timing of solid food introduction.
• Sleep more.
• Restrict video gaming and TV.

Slide 166

Prolonged Bottle Use

• Early Childhood Longitudinal Study, Ohio.
• 6750 children born in 2001.
• Bottle use at 24 months.
• Outcome: obesity at 5.5 years:
  • 22.9% (95% CI, 19.4-26.4%) in bottle-users.
  • 16.1% (95% CI, 14.9-17.3%) in non bottle-users.
  • OR 1.55 (1.27-1.90).
  • Adjusted OR 1.33 (1.05-1.68).

Gooze RA et al. Prolonged Bottle Use and Obesity at 5.5 Years of Age in US Children. J Pediatr 2011; 159: 431-6.

Slide 167

Introduction of Solid Foods

• Project Viva, Boston, prospective cohort study.
• 847 children.
• Maternal surveys of solid food introduction (<4 mos, 4-5 mos, 6 mos or older).
• Outcome: obesity at age 3 years.
• Stratified by breastfeeding status at 4 mos.

Huh SY, et al. Timing of Solid Food Introduction and Risk of Obesity in Preschool-Aged Children. Pediatrics 2011; 127; e544.

Slide 168

Introduction of Solid Foods

• Breastfeeding.
• Breastfeeding associated w/solid food introduction (p<0.0001).
  • 8% vs. 33% at <4 mos.
  • 17% vs. 9% at >6 mos.
• Breastfeeding associated with obesity at age 3.
  • 7% vs. 13%.

Image: A pie chart shows the following data:

• Breastfed: 67%.
• Never breastfed: 11.9%.
• Weaned at less than 4 months: 21.1%.

Slide 169

Introduction of Solid Foods

• Among breastfed infants, timing of solid foods was not associated with obesity at age 3.
• Among formula-fed infants, early or late introduction was associated with:
  • Obesity (OR 6.3 for early).
  • Weight.
  • Weight for age.
  • BMI [body mass index].

Slide 170

Crossing growth percentiles

• Multisite, longitudinal study.
• 44,622 children ages 1 month-11 years.
• Data points at 1, 6, 12, 18, 24 month visits.
• BMI at 5 and/or 10 years.
• Used Centers for Disease Control and Prevention (CDC) growth lines (5, 10, 25, 50, 75, 90, 95 %iles).

Taveras E, et al. Crossing Growth Percentiles in Infancy and Risk of Obesity in Childhood. Arch Pediatr Adolesc Med 2011; 165(11);993-8.

Slide 171

Crossing growth percentiles

• Crossing >2 weight-for-length growth lines:
  • 43% in first 6 mos.
  • 20% 6-12 mos.
  • 14% 12-18 mos.
  • 11% 18-24 mos.
• Obesity prevalence:
  • 11.6% at age 5.
  • 16.1 % at age 10.

Slide 172

Crossing growth lines

• Secondary analysis:
  • Obesity at age 5, OR 2.08 (1.84-2.34).
  • Obesity at age 10 OR 1.75 (1.53-2.00).

Image: A table compares prevalence of obesity at ages 5 and 10 years according to starting weight-for-length percentile and the number of weight-for-length percentile lines crossed.

Slide 173

Restricting video games

• 22 healthy normal-weight male 15-19 year old in Copenhagen.
• Randomized crossover design:
  • 1 hour seated xBox play.
  • Relax in a comfortable chair.
• No difference in:
  • Appetite/hunger sensations.
  • Insulin concentration, cortisol, ghrelin.
  • Eating time.
  • Compensatory food intake changes (+436 kJ).
• Significant differences:
  • Heart rate, blood pressure (p<0.01).
  • Sympathetic tone (LF/HF ratio) (p<0.05).
  • Mental workload (p<0.01).
  • Plasma glucose (p<0.01).
  • Energy expenditure +89 kJ (p<0.01).
  • Energy intake +335 kJ (p<0.05).

Chaput J, et al. Video game playing increases food intake in adolescents: a randomized crossover study. Am J Clin Nutr 2011; 93: 1196-1203.

Slide 174

Sleep more

• Cohort study, New Zealand.
• 244 children age 3-7.
• Sleep duration measured age 3-5.
• Outcomes @ age 7: for each additional hour of sleep between ages 3-5:
  • Reduction of BMI of 0.48 (0.01-0.96).
  • RR of overweight 0.39 (0.24-0.63).

Carter PJ, Taylor BJ et al. Longitudinal analysis of sleep in relation to BMI and body fat in children: the FLAME study. BMJ 2011;342:d2712.

Slide 175

What about beta-blockers in chronic obstructive pulmonary disease (COPD)?

Slide 176

• 6000 COPD patients.
• Retrospective cohort study.
• 819 taking a beta-blocker.
• Mean age 69.
• After 4.4 year follow-up:
  • 1/3rd died.
  • Beta blocker use associated with a 22% decrease in all cause mortality.
  • No adverse effects on lung function.
• Other similar studies:
  •  BMJ 2011 May 10; 342:d2549. (http://dx.doi.org/10.1136/bmj.d2549).

Rutten FH et al. Β-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med 2010 May 24; 170:880.

Slide 177

Metformin causes B-12 deficiency

• 390 patients randomized to Insulin + metformin or Metformin + placebo.
• 19% lower B12 levels.
• 7% had true B12 deficiency.
• 11% low B12 levels.
• So, think about this as a cause of neuropathy in those on metformin.

BMJ 2010 May 20; 340:c2181