28th Annual Best Science Medicine Course · 2018. 5. 22. · Research glutamate and adenosine...

April 7th and 8th, 2017

Fairmont Waterfront Hotel Vancouver, B.C.

Presented by

COURSE DIRECTORSDrs. James McCormack, G. Michael Allan and Robert Rangno

COMMITTEE MEMBERSDrs. Rita McCracken and Tracy Monk

SATURDAY Syllabus

28th AnnualBest Science Medicine CourseFormerly the Drug Therapy Decision Making Course – 25 years

"It is an art of no little importance to administer

medicines properly; but it is an art of much

greater and more difficult acquisition to know

when to suspend or altogether omit them."

Philippe Pinel 1745‐1826

The New Therapeutic Commandments

Thou shalt

1. Have no aim except to help patients according to their goals

2. Always seek knowledge of the benefits, harms, and costs of

treatment

3. If all else fails consider watchful waiting

4. Honour balanced sources of knowledge

5. Treat according to level of risk and not to level of risk factor

6. Not bow down to treatment targets

7. Honour thy elderly patient

8. Not pile one treatment upon another

9. Diligently try to find the best treatment for the individual

10. Start with the lowest dose possible

Written by R Lehman, J McCormack, T Perry, A Tejani, J Yudkin

Best Science Medicine Course 2017 FACULTY Course Committee Co-Chairs: Bob Rangno, Emeritus Prof., Medicine, Pharmacology, UBC & PHC James McCormack, Prof., Pharmaceutical Sciences, UBC G. Michael Allan, Prof., Family Medicine, University of Alberta & Director, Evidence and CPD Program, Alberta College of Family Physicians Committee: Rita McCracken, Clin. Assist. Prof., Medicine and Associate Head, Family Medicine, PHC Tracy Monk, Clin. Assist. Prof., Medicine, UBC Guest Faculty Alan Cassels, Adj Prof., Human and Social Development, University of Victoria Tina Korownyk, Assoc. Prof., Family Medicine, University of Alberta Adrienne Lindblad, Assoc. Clin. Prof., Family Medicine, University of Alberta &Knowledge Translation and Evidence Coordinator, Alberta College of Family Physicians Local Faculty Keith Ahamad, Clin. Asst. Prof., Family Medicine, UBC & PHC Claire Hinnell, Clin. Asst. Prof., Medicine, Neurology, UBC Victor Leung, Clin. Assoc. Prof., Path Lab Med., UBC & PHC Peter Loewen, Assoc. Prof., Pharm. Sciences, UBC & VCHA Julian Marsden, Clin. Prof., Emerg. Medicine, UBC & PHC Kam Shojania, Clin. Prof., Medicine, Head, Rheumatology, UBC & PHC John Stewart, Emeritus Prof., Medicine, Neurology, McGill University; Retired Neurologist, UBC & LGH Aaron M Tejani, Clin. Asst. Prof., Pharmaceutical Sciences, UBC Helen Tremlett, Prof. Medicine, Neurology, & Canada Research Chair in Neuroepidemiology and Multiple Sclerosis, UBC FHA – Fraser Health Authority LGH – Lions Gate Hospital PHC – Providence Health Care UBC – University of British Columbia VCHA – Vancouver Coastal Health Authority VGH – Vancouver General Hospital

BSMC 28th Annual Best Science Medicine Course Formerly The Drug Therapy Decision Making Course – 25 years

C O U R S E

SATURDAY, APRIL 8, 2017 07:30 Registration (Coffee & Muffins) Chairs – Mike Allan and James McCormack

“Be-all and the end-all” (Macbeth) MOVEMENT ISSUES 08:30 Tips for Treating Parkinsonism – “Bring him festinately hither” Claire Hinnell 08:50 The curse of spinal stenosis – “Thou shalt be pinched” John Stewart 09:10 Multiple sclerosis – “A dagger of the mind, a false creation” Helen Tremlett 09:30 Questions 09:50 Refreshment Break

“Naked truth” (Love’s Labour’s Lost) A GEMISH 10:10 Drugs in pregnancy Adrienne Lindblad 10:30 Putting our “best foot forward” by doing the right thing, choosing wisely, etc. Alan Cassels 10:50 Questions 11:10 “The short and the long of it” – Top 10 studies that you need to know about Tina Korownyk / Mike Allan 11:30 Questions 11:50 Lunch

“There’s a method to my madness” (Hamlet) ENOUGH SAID 12:40 “Age, with his stealing steps, Hath clawed me in his clutch.” Top things we screw up with the elderly. Rita McCracken 13:10 Guidelines – “Neither rhyme nor reason” James McCormack 13:40 “What’s done is done” how to implement all this new knowledge The Gang plus the Audience 15:00 “Parting is such sweet sorrow” (Romeo and Juliet) AND “Good riddance” (Troilus and Cressida)

Tips for Managing Parkinson’s Disease

April 8, 2017Dr Claire Hinnell

Surrey, BC

Faculty/Presenter Disclosure

Faculty: Dr Claire Hinnell

Relationships with commercial interests:

Honoraria: Abbvie Inc.

Disclosure of Commercial Support

This program has received financial support from no one.

This program has received in‐kind support from no one.

Potential for conflict(s) of interest: Dr Hinnell has received honoraria from Abbvie Inc. whose product

Duodopa is being discussed in this program.

Mitigating Potential Bias

Duodopa is Health Canada approved for treatment of advanced Parkinson’s disease.

Dr Hinnell will remind the audience of previous honoraria received from Abbvie when mentioning the use of intrajejunal l‐dopa infusion therapy in PD and will present only the current available scientific evidence for its use.

Learning Outcome Objectives

1. Be able to describe the medication classes used in treating PD and outline their indications in addressing motor symptoms

2. Be able to describe the commonly held myths in PD treatment

3. Be able to identify and begin to address non-motor symptoms in patients with PD

4. Be able to generally discuss alternative and invasive therapies with patients with PD

Impact of PD

Canada – 100,000

BC - 12,500

By 2030, # in BC over 65 yrs with PD – 15,000

Claire Hinnell

Symptoms

Tips for Managing PD

1. Meds in PD: the basics

2. Meds in PD: the myths

3. Meds in PD: the tricks

4. DonÕt forget the non-motor symptoms

5. A few interesting tidbits and recent research1. Alternative therapies

2. Marijuana

3. Invasive therapies

Meds: the Basics

DOPAMINE

Levodopa-carbidopa

Levodopa-benserazide

DOPAMINEAGONISTS

Pramipexole

Ropinirole

Rotigotine patch

Bromocriptine

MAOB-I

Rasagiline

Selegiline

Add on Medications

Entacapone

Trihexiphenidyl

Amantadine

COMT-I

• l-dopa• MAOB-I• DA

• higher dose• increased

frequency

• l-dopa• DA• COMT-I• MAOB-I

• DBS• continuous

intraduodenalinfusion

Increasing dyskinesias

Delayed onWearing off

Meds: the myths

Claire Hinnell

Myth

Levodopa accelerates disease progression

Reality: Levodopa has been shown to increase lifespan and dramatically improve quality of life. Levodopa is associated with less worsening of PD symptoms than placebo consistent with a slowing of disease progression.

Levodopa and the progression of PD. NEJM 2004; 351:2498-2508. ELLDOPA study.

Myth

Levodopa stops working after 5 years… so we need to save it for later

Reality: Levodopa works for decades. Levodopa does not treat all of the symptoms of PD, but it dramatically helps many of the most disabling motor symptoms. After years of symptoms and levodopa tx, the responses may be less dramatic or consistent but levodopa continues to provide substantial benefit.

Myth

Levodopa causes dyskinesias so we need to try to delay the use of levodopa as long as possible.

Reality: Treatment-related side effects are less with levodopa.

PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. The Lancet - 11 June 2014

Approach to starting

more emphasis on long-term considerations to guide early treatment

longer life expectancy and are more likely to develop motor fluctuations and dyskinesias

less emphasis is placed on long-term considerations

focus is on providing adequate symptomatic benefit in the near term, with as few adverse effects as possible

Younger Older, cognitive impairment

In a nutshell

levodopa more robust effect

DA generally more side effects which increase with age (somnolence, hallucinations, peripheral edema, ICD)

motor complications occur earlier with levodopa

Meds: the tricks

Start slow, go slow –> L-dopa is the best we’ve got

Domperidone can help pts get over the hump (*Health Canada guideline for cardiac s/e)

Claire Hinnell

Motor fluctuations

wearing off

increase L-dopa dose

increase L-dopa frequency

add MAOB-I*

add entacapone**

delayed kick-in

chew, dissolve or crush tablets

*MOAB-I and antidepressant –NOT contraindicated, exceedingly low risk of serotonin syndrome but inform patient of S&S**entacapone tablets can be split in half

Richard et al. Neurology. 1997; 48(4):1070-7.Panisset et al. AAN 2011 Poster. STACCATO study.Montgomery et al. 2009. Int Congress of PD & MD. Poster.Teva pharmaceutical industries data on file.

Dyskinesias

remember who you’re treating

Meds

reduce individual dose or dosing frequency

add DA & reduce l-dopa

amantadine (s/e esp. in elderly)

off-label, small studies

mirtazapine

buspirone

propranolol

levetiracetam

Invasive

DBS

intrajejunal continuous l-dopainfusion

Research

glutamate and adenosine antagonists

marijuana – evidence so far is NO

Guridi et al. Clinical features, pathophysiology, and treatment of l-dopa-induced dyskineasis in PD. Parkinson’s Disease 2012

“Bring him festinately hither”

start hesitation freezing

festination falls

FoG in PD

FoG: sudden inability to voluntarily initiate stepping movements

little robust evidence….expert opinion currently rules

reality: try increase l-dopa (level B), falls prevention, physiotherapy/education

• consider MAOB-I• start or increase l-dopa• if dyskinesias->DBS• intraduodenal l-dopa

gel

• try droxidopa* and entacapone

• ? cholinesterase inhibitors

• taper dopaminergic tx• if can’t, DBS first

Freezing of Gait: a practical approach to management. Lancel Neurol 2015;14:768-78.

Falls in PD

donepezil shown to reduce falls in 23 advanced patients

rivastigmine in PD pts without dementia can improve gait stability

might reduce fall frequency

rivastigmine in PD pts with MCI or dementia better MoCA and lower falls rate in tx group vs placebo

Rivastigmine for gait stability in patients with PD (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 March; 15(3):249-258.

Effects of a central cholinesterase inhibitor on reducing falls in PD. Neurology 2010 Oct5;75(14):1263-9.

Impact of rivastigmine on cognitive dysfunction and falling in PD pts. EurNeurol. 2015; 74(1):86-91.

Moving along…

Claire Hinnell


1. Meds in PD: the basics and a few tricks



4. A few interesting tidbits and recent research1. Marijuana


IMPORTANT

Unidentified or untreated non-motor symptoms contribute to poorer quality of life and poorer motor function overall

Non-motor symptoms

What PD patients face…PD survivors at 15 yrs

95% end of dose failure, l-dopa induced dyskinesia

80% falls

80% cognitive issues

50% hallucinations

50% depression

50% choking

40% urinary incontinence

35% symptomatic postural hypotension

40% in long term care

Sydney Multicenter Study of PD: non-L-dopa-responsive problems dominate at 15 years. Mov Disord. 2005 Feb;20(2):190-9.

Urinary, bowel, sexual dysfunction

avoid oxybutynin (cog s/e)

be aggressive - constipation affects QoL but also med absorption and efficacy

find and tx the underlying reason(s)

phosphodiesterase inhibitors may help

Claire Hinnell

Postural hypotension

WHY

Parkinson’s disease

levodopa/dopamine agonist

Other comorbid conditions

Other medications

TREATMENT

Reduce causative meds

High salt diet

Stockings

Domperidone

Fludrocortisone, midodrine(watch supine HTN)

Mood

GREATEST DETERMINANTOF QoL

• Not just sad…often irritability

• Be open and aggressive in treating mood disorders

• If mood is left untreated, motor symptoms are difficult to treat

• +ive trials: CBT, nortriptyline, desipramine, citalopram, paroxetine, venlafaxine

• commonly used: SSRIs, SNRIs, mirtazapine

Comparison of desipramine and citalopram treatments for depression in PD: a double-blind, randomized placebo-controlled study. MovDisord. 2008 Apr 30;23 (6): 850-7.A randomized, double-blind, placebo-controlled trial of antidepressants in PD. Neurology. 2012 Apr 17;78(16):1229-36.A controlled trial of antidepressants in patients with PD and depression. Neurology. 2009 Mar 10;72(10):886-92.

Sleep

Medication s/e reduce meds, esp. cholinergic or DA

PD motor symptoms qhs or overnight l-dopa

Restless leg syndrome DA,clonazepam, GBT

REM sleep disorder melatonin, clonazepam

Vivid dreams avoid qhs l-dopa/DA, quetiapine

Anxiety SSRI, SNRI, mirtazipine

Bladder meds, urinals, urology

Sleep apnea low threshold to assess, tx

Psychosis

Cognitive Issues

25% of newly diagnosed PD patients

80% of late-stage PD patients

Problems: Multi-tasking, visuospatial, executive function (not AD)

• Be alert for other causes• med side effects (eg: amantadine, benzo’s etc.)• delirium – screen for UTI etc.

• Cholinesterase inhibitors are beneficial for select patients• for mild to moderate dementia• may increase tremor• do not worsen falls

• Rivastigmine = only one licensed for PD dementiaCholinesterase inhibitors for PD: a systematic review and meta-analysis. JNNP 2015; 86 (7)

PsychosisEtiology

PD related PD psychosis PD meds Pain Sleep disorder

***organic delirium Infection - UTI, pneumonia Metabolic

Other medications Opioids

Pain – other causes

Psychosis Tx in PDReducing medications in order:

Next step: Antipsychotics

Claire Hinnell

Antipsychotics in PD

Recommendations: quetiapine – no RCTs, 2 trials negative (1,2)

clozapine – only drug with evidence but issues of a/e (3,4)

Typical antipsychotics – worsen PD motor symptoms

Pimavanserin – phase III evidence (5)

Cholinesterase inhibitors – may have antipsychotic properties in pts with PD dementia (6)

Psychosis References

1. Ondo et al. Double-blind, placeb-controlled, unforced titration paralllel trial of quetiapine for dopaminergic-induced hallucinations in PD. Mov Disord 2005;20:958-63.

2. Rabey et al. Effect of quetiapine in psychotic PD patients: a double-blind labeled study of 3 months’ duration. Mov Disord 2007;22:313-318.

3. Clozapine in drug-induced psychosis in PD. The french Cloapine Parkinson Study Group. Lancet. 1999;353:2041-2.

4. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. NEJM. 1999;340:757-63.

5. Pimavanserin for patients with PD: a randomised, placebo-controlled phase 3 trial. Lancet 2014; Feb; 83:533-540.

6. Successful use of donepezil for the treatment of psychotic symptoms in patients with PD. ClinNeuropharmacol. 2002;25:107-10.






2. Marijuana


Alternative treatments

Coenzyme Q10

negative trial (1)

Fava beans or Mucuna puriens

‘natural l-dopa’

Caffeine (2)

trial on sleep in PD showed beneficial effect on

motor symptoms

Medical marijuana

survey of PD experts (3) 95% asked to prescribe it

52% took a neutral position, 9% discouraged its use, 39% encouraged it

most expected it would worsen motivation, sleep, hallucinations

most feared s/e on STM, LTM, executive function ,driving

Sid effects (4,5) hypotension, vertigo, visual hallucinations, dizziness and

somnolence

weakness, mood and/or behaviour changes

Medical marijuana

uncontrolled studies suggest benefit

few controlled studies - inconsistent results 4 controlled studies (small)

no benefit on motor symptoms

mixed results on dyskinesias

mixed results on QoL

Systemic review 2014 by AAN (4) probably ineffective for MS-related tremor

probably ineffective for levodopa-induced dyskinesias in PD

2015 review in MD journal (5) data insufficient to draw conclusions

Claire Hinnell

Alternative therapyreferences

1. Beal et al. Parkinson Study Group QE3 Investigators. A RCT of high-dosage coenzyme Q10 in early PD: no evidence of benefit. JAMA Neurol. 2014 May;71(5):543-552.

2. Postuma et al. Caffeine for treatment of PD. Neurology 2012; 79: 651-658.

3. Bega et al. Medicinal cannabis for PD: practices, beliefs, and attitudes among providers at National Parkinson Foundation Centers of Excellence. Movement Disorders 2016; 90-95.

4. Gloss et al. Systematic Review: Efficacy and safety of medical marijuana in selected neurologic disorders. Neurology 2014;82:1556-1563.

5. Kluger et al. Review of Cannabinoids in Movement Disorders. Mov Disord. 2015; 30(3): 313-327.

Deep Brain Stimulation

• 50% improvement in mobility and on-time

• 75% reduction of dyskinesias

Intrajejunal levodopa infusion

levodopa/carbidopa in gel form delivered directly into the jejunum through PEG tube

more constant levodopa dose throughout day

reduces off time and fluctuations

Double-blind, double dummy, randomized study of continuous intrajejunal infusion of levodopa-carbidopa intestinal gel in advanced PD. Lancet Neurol. 2014 Feb;13(2):141-9.

Intrajejunal levodopa infusion

Adapted from: Olanow CW et al. Poster Presentation # P411 presented at the Movement Disorder Society’s 16th International Congress of Parkinson’s Disease and Movement Disorders, Dublin, Ireland, June 17-21, 2012.

Focused Ultrasound

Essential tremor 3 mo – reduced tremor 47% vs 0.1% 12 mo – improvement in thalamotomy grp maintained s/e – gait disturbance and paresthesias Health Canada and FDA approved sites in Toronto and building in Calgary

Tremor dominant PD enrolment closed for study on VIM thalamotomy in PD

PD dyskinesias study ongoing using focused ultrasound to lesion Gpi

NEJM 2016; 375: 730-739, August 2016: A Randomized trial of focused ultrasound thalamotomy for essential tremorhttps://www.fusfoundation.org/diseases-and-conditions/neurological/parkinsons-disease






2. Marijuana


Claire Hinnell

Thank you

Claire Hinnell

The Curse of (Lumbar) Spinal Stenosis - LSS

Disclosures

• John Stewart MBBS, FRCP

• Relationships with commercial interests:

Consulting Fees: IMEs for legal firms and ICBC

• Commercial Support: None

• Conflicts of interest: None

• Sources of bias: None! Spine doctor and spine patient

Disclosures (revelations!)

2012 2014

• To make you experts in diagnosing LSS

• Help you differentiate it from other lumbar spine disorders

• Understand treatment options


WHY SHOULD YOU BE INTERESTED IN LSS?

• Increasingly common age

• N. America – commonest reason for spinal surgery > 65 years

THE AGENDA: 6 QUESTIONS

1 Definition of degenerative LSS?

2 Most important symptoms & signs of LSS?

3 Best diagnostic tests?

4 Natural history of symptomatic LSS?

5 How effective are non-surgical treatments?

6 How effective is surgery?

John Stewart

Diminished space available for the neural and vascular

structures in the lumbar spine secondary to degenerative

changes in the spine

LSS Definition diminished space available for the neural and vascular structures in the lumbar spine secondary to degenerative changes in the spine

characteristic clinical sxs clearcut imaging abN’s+

Clinical LSS Definition

The 2 important “holes” in the spine

1.Central spinal canal

facet joint

The 2 important “holes” in the spine

2. Nerve root foramen

nerve root

“attack from on all sides and with all weapons…”

facet joint facet joint

disc

John Stewart

Lateral recess/nerve root foramen→ root compression

Central canal → cauda compression

LSS is a very heterogeneous disorder

claudication radiculopathies

Most important symptoms and signs

• Low back, buttock pain

• Standing, walking → worse, often spreads

to legs, then +/- numbness and weakness legs.

Improved by sitting for minutes

• Also improved by forward flexion

• +/- permanent numbness and weakness

VIGNETTE

• 65 yr cardiologist. Very active walking, tennis, squash

• Increasing but tolerable low back pain

• Walking 1 block → buttock and thigh pain; diffuse numbness legs. Standing > 10 minutes ditto. Relieved by sitting x 5 minutes. (cauda equina or spinal claudication)

• Tennis and squash worse, but if leans forward could still play.

• Shopping with trolley, riding bike OK

• Facet joint pain

• SI joint pain

• “Crummy” back pain +/- other reasons

for walking intolerance eg dyspnea

• Hip pain

Beware of the masqueraders!

Clinical pearl: send the patient for a walk

Examination

Hip joints fine

Often no neuro deficits

Best diagnostic tests for LSS?

CT scan good but MRI better

John Stewart

L3,4

L 4,5

L5, S1

L3,4 L4,5 L5,S1

Beware!• Many older patients can have severe central stenosis on imaging and

NO symptoms

(References here exceed 2 Power Point slides in unreadable font size………)

So….

characteristic clinical sxs clearcut imaging abN’s+

LSS Diagnosis

YOUR RECOMMENDED MANAGEMENT?

Conservative?Surgery?

What else do you need to knowto decide?

3 things you need to know

1. Natural history?

2. Efficacy of conservative measures?

3. Efficacy of surgery?

COCHRANE REVIEWS

their critical limitations – to be discussed

John Stewart

1. Natural history of symptomatic LSS?

Evidence:

No good evidence to define the natural history of clinically or radiologically severe LSS

Opinion:

• Patients with mild & tolerable sxs – remain same or slowly worsen over years

• Moderate sxs – worsen over months or few years

• Those with severe & intolerable sxs – danger of paraplegia

• Exercise/physio

• Epidurals etc

• Chiropractic

• Naturopathic

• Spinal decompression

• Laser technology

2. Are “conservative” treatments effective for symptomatic LSS?

Ammendolia et al: ; Eur Spine J ; 23:1282 1301

+ other sources:

NO EVIDENCE – but studies are all of poor quality

3. Is surgery effective?

Zaina, F et al. Surgical vs. non-surgical treatment for LSS. 2016

“We have very little confidence to conclude whether surgical treatment or conservative approach is better for LSS, and can provide no new recommendations to guide clinical practice.”

Note side effects surgery >> conservative (elderly population)

SO! The cardiologist: Would you refer for surgery? Post-surgery

• Could walk many km’s

• Stand x hours

• Back to being a “killer”

on the squash and tennis courts

John Stewart

Is surgery effective? OPINION!

• Classical & life-interfering sxs

• Masqueraders excluded

• Imaging = severe central stenosis

• (? Neuro/EMG deficits)

• Surgery effective in > 50% (opinion!)

• Most important symptoms: Spinal claudication syndrome,

not just low back pain, +/- radiculopathy sxs.

• Signs: normal or root damage

• Best diagnostic tests: MRI, CT: beware – many false +ves

• Non-surgical interventions generally ineffective

• Is surgery effective? Yes, but carefully select patients

• Criteria for surgery = bad sxs, bad stenosis

TAKE-HOME MESSAGES

THE END

John Stewart

“A dagger of the mind, a false creation” Multiple sclerosis, a search for truth:

Using population-based data linkages to investigate ‘real-world’ drug safety and effectiveness

Helen Tremlett, PhDCanada Research Chair in Neuroepidemiology and MS

Professor, Faculty of Medicine (Neurology)

University of British Columbia, Vancouver

28th Annual Best Science Medicine Course Saturday April 8th 2017. Vancouver

Faculty DisclosureHelen Tremlett, Professor Canada Research Chair in Neuroepidemiology & MS

Relationships with commercial interests in prior 5‐years:

Grants/Research Support, Speakers Bureau/Honoraria, Consulting Fees, Other: None

Philosophy/ approach:

Obtain research funds from non‐pharm. industry sources to allow independent pharmacovigilance program

Managing Potential Bias

Decline honorarium related to speaking engagements

Report generic drug names

Welcome feedback if bias perceived in presentation – please be specific

The field of MS drug therapeutics is rapidly evolvingBut MS is not a rapidly progressing disease

1990’s – no MS drugsToday >14

Approved based on short‐term RCTs in limited groups of select patients

Outline / ObjectivesGain insight into the challenges surrounding drug safety and effectiveness studies in MS and the value in using population‐based data linkages

• Do the MS disease modifying drugs (beta‐interferon) impact long‐term disease progression in clinical practice?

• What about drug safety?

Does beta‐interferon alter cancer risk in MS?

What about other adverse events?

Optional slide on MS“This disease is beyond my practiceMore needs she the divine than the physician” [Dr, Act V]

Multiple sclerosis (MS)

• Chronic disease of the brain and spinal cord

• North America is a ‘high risk’ area; ≈1 in 500 have MS

• Typical age of onset: 20‐40 years

• Women affected more than men (75% women)

• Most common cause of neurological disability in young adults,

aside from trauma

• Highly variable disease

• No known cause or cure

Optional slide on MS

Helen Tremlett

OutlineGain insight into the challenges surrounding drug safety and effectiveness studies in MS and the value in using population‐based data linkages






British Columbia, Canada

Population 4.7 million13% of Canadian population3rd most populous province/territory in CanadaLandmass: four times size UK

Example: health administrative and clinical data linkagein Canada e.g. British Columbia

Study Cohort: individuals with MS and general population controls

Physician claims

Hospital Separations

Data

Prescription data

Census Geo Data

Vital statistics

Registration files

MS, comorbidity, morbidity, health service utilization

Birth & death information

Residency & demo‐graphic

Drug exposure

Income Data [SES]

Study Cohort: individuals with MS and general population controls

Physician claims

Hospital Separations

Data

Prescription data

Census Geo Data

Vital statistics

Registration files

MS, comorbidity, morbidity, health service utilization

Birth & death information

Residency & demo‐graphic

Drug exposure

Income Data [SES]

201750,000 MS 220,000 controls

Example of MS studies

Drug safety and effectiveness

Pregnancy outcomes in MS

Impact of parental MS and childhood development

Cancer risk in MS

Incidence and prevalence of MS

Pharmaco‐genomics

Comorbidity & MS – incidence, prevalence & impact

Life expectancy in MS

Factors influencing disease progression

Prodromal MS

Cardiovascular disease & MS

Example: data linkage in Canada e.g. British Columbia






“Fair is foul and foul is fair. Hover through the fog and filthy air” [Witches, Act I]

Cochrane review. 2015 15 MS drugs; 39 RCTs

‘For preventing irreversible disability worsening, insufficient evidence is currently available.’

‘Most …studies were sponsored by pharmaceutical companies…a known potential source of bias.’

Solution: examine irreversible disability worsening in an independently funded study

Helen Tremlett

ObjectiveExamine association between beta‐interferon exposure and disability progression in RRMS treated in clinical practice, British Columbia, Canada

A great team* [*evil witches not included]

AfsanehShirani

John Petkau

Paul Gustafson

Joel Oger

Yinshan Zhao Ehsan Karim

Charity Evans

Elaine Kingwell

Mia van derKop

Clinical trials measure ‘efficacy’ Our ‘real‐world’ study measures ‘effectiveness’

Effectiveness“Does the drug

work?”

Efficacy“Can the drug

work?”

Afsaneh Shirani, JAMA 2012

How did we measure ‘disability progression’?

0 1.512.5

3.54.5

5.56.5

7.5

8.5

9.510

9

76

54

23

8

6

Afsaneh Shirani, JAMA 2012

Flying ability not assessed Generalizability to Macbeth’s witches: nil

Observational study: one IFNβ treated groupand two ‘control’ groups:

Apr 1, 1985 Jul 1, 1995 Dec 31, 2008

Treated cohort

Contemporary untreated cohort‘eligible for drug, but did not take’

Historical untreated cohort‘eligible for drug treatment, but no drugs available’

Dec 31, 2004

Afsaneh Shirani, MD

n=959

n=829

n=868

Multivariable Cox regression IFNβ a time‐varying covariate

Adjusted: age, sex, disease duration, EDSS, SES, co‐morbidities

Observational study: one IFNβ treated groupand two ‘control’ groups:

Apr 1, 1985 Jul 1, 1995 Dec 31, 2008

Treated cohort

Contemporary untreated cohort‘eligible for drug, but did not take’

Historical untreated cohort‘eligible for drug treatment, but no drugs available’

Dec 31, 2004

Afsaneh Shirani. JAMA 2012

n=959

n=829

n=868

Multivariable Cox regression IFNβ time‐varying covariate

Also, propensity score adjustment

Linked to health administrative databases*

Adjustments: age, sex, disease duration, baseline EDSS, *SES, *co‐morbidities

Helen Tremlett

0.5 1 20.2 5

Main finding: No strong association between β‐IFN exposure and disability progression in patients with relapsing‐remitting MS

0.1 10

HR=1.30 (95% CI: 0.92 ‐1.83)for contemporary approach

HR= 0.77 (95% CI: 0.58‐1.02)for historical approach

Afsaneh Shirani, MD.

• Findings relevant for future observational study design

‐ ‘indication bias’ evident when contemporary controls included[age, sex, disease duration, EDSS, socioeconomic status, co‐morbidities & propensity score

adjustments]

historical controls maybe more appropriate than contemporary controls

Adjusted Hazard Ratio (95% CI). Outcome: EDSS 60.5 1 20.2 50.1 10



Adjusted Hazard Ratio (95% CI). Outcome: EDSS 6

Similar findings with advanced marginal structured models………..

Main finding: No strong association between IFNβ exposure and disability progression in patients with relapsing‐remitting MS

Ehsan Karim et al. Am J Epi 2014 ; ‘top 10 paper of the year award’

……..first to consider MS relapses as a time‐varying confounder

Shirani, JAMA 2012

0.5 1 20.2 50.1 10



Afsaneh Shirani, MD.

Adjusted Hazard Ratio (95% CI). Outcome: EDSS 6

Implications: Does not mean drug is ineffective for all…. …..need more accurate selection of potential responders?

But, findings are consistent with extended clinical trials e.g:16‐year follow‐up (Ebers. JNNP 2010)

CIS BENEFIT study (Kappos Lancet Neurol 2009)N. American SPMS (Neurology 2004)

Allows more realistic expectations on potential β‐IFN benefits

Main finding: No strong association between β‐IFN exposure and disability progression in patients with relapsing‐remitting MS

‘Hours dreadful and things strange’ [Old Man, Act 2]

The downsides of MS drugs: what do we know?

• ‘short‐term trials provide scanty and poorly reported safety data…do not provide useful evidence….to obtain a reliable risk profile’

Cochrane review 2015

• ‘….(beta‐interferons) long‐term safety has not been systematically assessed.’

Freedman. Can J Neurol Sci 2013

Solution: examine drugs safety using comprehensive population‐based data linkages

Potential adverse event

IFN‐β ever exposed case/control (n)

Age adjusted Odds Ratios (95% CI)

Stroke 106/1688 1.8 (1.2‐2.9)

Migraine 279/4969 1.6 (1.2‐2.0)

Depression 842/14099 1.3 (1.1‐1.6)

Haematologicalabnormalities

294/5370 1.3 (1.0‐1.7)

Association between IFN‐β exposure (vs. no exposure)and potential adverse events

“Oh, full of scorpions is my mind” [Macbeth, Act III]

“..this most bloody piece of work” [MacDuff, Act II]

Hilda De Jong, Paper under review

Strengths and limitations

“Our castle’s strength” [Macbeth, Act 5]

• ‘Real world’ clinical practice based setting• Systematically assessed potential adverse events• Access to all hospital, physician and drug exposure data

“Poor prattler, how thou talk’st!” [Lady MacDuff, Act 4]

• Could not consider self‐limiting adverse events e.g. ‘flu‐like symptoms’

• No access to health behaviours or lifestyle factors• Potential for detection bias

Helen Tremlett






Clinical observation: “My female MS patients who took beta‐interferon now present with breast cancer. Is there a link?”

“Out, damned spot! Out, I say!” [Lady Macbeth Act 5]

Population‐based study: ‘No evidence that cancer risk was altered after exposure to IFNB over a 12‐year observation period’

Nested case‐control 48,705 patient‐years, 5,146 RR‐onset MS developed 227 cancers IFNB exposure and overall cancer risk:OR: 1.28; 95%CI: 0.87 ‐ 1.88

Trend for breast cancer risk: OR: 1.77; 95%CI: 0.92 ‐ 3.42But no evidence of a dose‐response effect

Kingwell, JNNP 2014

“Might be the be‐all and the end‐all here” [Macbeth, Act 1]

Summary:Gain insight into the challenges surrounding drug safety and effectiveness studies in MS and the value in using population‐based data linkages


• What about drug safety?Does beta‐interferon alter cancer risk in MS?


No strong association found in the clinical practice setting…..…currently investigating other outcomes & other drugs

No strong evidence that IFN-β exposure alters cancer risk

IFN-β associated with 1.8 & 1.6-fold increase risk stroke & migraine1.3-fold increases in depression & haematological abnormalitiesProvides new insights into the benefit-risk ratio in ‘real-world’ setting

UBC MS Neurologists: D.AdamsD.CraigL. Daly

V. DevonshireS. Hashimoto

J HoogeO. Hrebicek

B. JonesL KastrukoffS.Meckling

J OgerD. PartonD. Paty

AL SayaoP Smyth

W. ShtybelT Traboulsee

Research, Support staff and patients Jon Money, Database Manager

MS Clinic patients, nurses and staff MS Clinical Trials Research Group

Funding:

Pharmacoepidemiology in MS (PiMS) Research Group Anna‐Marie BuenoHilda de JongTom DugganCharity EvansEhsan KarimElaine KingwellKaarina KowalecBonnie LeungEllen LuKyla McKayNeda RazazAfsaneh ShiraniStacey TkachukMia van der KopTingting ZhangYinshan ZhaoFeng Zhu Funding:

A team approach

Questions?

Thank you

Interested? Opportunity: graduates, postdocs, visiting fellows, collaborations…

Helen Tremlett

Drugs in Pregnancy: Feeling Queasy

Adrienne J Lindblad BSP, ACPR, PharmD

Knowledge Translation and Evidence Coordinator,

Alberta College of Family Physicians

Associate Clinical Professor,

Dept. of Family Medicine

University of Alberta


• Faculty/Presenter: Adrienne Lindblad

• Relationships with commercial interests:• Grants/Research Support: None

• Speakers Bureau/Honoraria: None

• Consulting Fees: None

• Other: Employee of Alberta College of Family Physicians, other funds from non‐profit organizations (Towards Optimized Practice)

Disclosure

• Some SSRI slides courtesy of Tina Korownyk

Learning Objectives

• By the end of this session, participants will be able to:

• Deliberate on the efficacy and safety of 4 medications for nausea and vomiting in pregnancy (ondansetron, doxylamine/pyridoxine, pyridoxine, ginger).

• Describe the evidence for fetal cardiac harm of SSRI use in pregnancy.

• Discuss with a patient whether omega‐3’s in pregnancy can decrease atopy in offspring.

Perspective

• ~4% babies born with major congenital birth defect

• 65% have unknown etiology

• “chemically induced” defects (including drug exposure) “probably account for <1% of all birth defects”.

• ~20 drugs or groups of drugs are recognized as increasing risk when used clinically in humans.

5https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071645.pdfaccessed 15‐MAR‐2017

• Recall bias

• Predisposition bias

• Detection bias• Example: 30% increase ultrasounds on SSRIs

• Sample size inadequate

• Severity of malformations unknown

• Data on spontaneous abortions rare

Clin Ther. 2007;29:918‐26.

Adrienne Lindblad

Nausea and Vomiting of Pregnancy Diclectin

• Five systematic reviews on antihistamine safety, 22‐37 observational studies, 17,00‐50,000 women exposed to antihistamines.1‐5

• No risk of fetal malformations with doxylamine [example OR=0.94 (0.80‐1.10)].2

• 4 systematic reviews have industry connections.1,3‐5

• Childhood cancer: 2 case‐control studies, increased risk with longer use (ie. >10 weeks), but no risk when based on mother‐reported use.

1Am J Perinatol. 1997 Mar;14(3):119‐24.2Am J Perinatol. 2014 Sep;31(8):701‐10. Epub 2013 Dec 9.3Drug Saf. 2016 Nov 22. [Epub ahead of print]4Drugs. 2000 Apr;59(4):781‐800.5Teratology. 1994 Jul;50(1):27‐37.

But does it work?

• Industry‐sponsored (n=259), placebo‐controlled, double‐blind RCT:1

• Statistically different mean change in 15‐point nausea and vomiting scale at day 15: ‐0.90 (‐1.55, ‐0.25). Clinical significance unknown

• No significant change in individual nausea, vomiting or retching scores.2

• 1 point improvement on 10‐point global assessment (2.8 versus 1.8).

• More compassionate use requests after study over (48.9% versus 32.8%)

• Potential selective reporting of outcomes.1Am J Obstet Gynecol. 2010;203:571:e1‐7.2Am J Obstet Gynecol. 2016 May;214:664‐6.

But does it work?

• Industry sponsored (n=2359) from 1970’s; 8 arms (pyridoxine, doxylamine, dicyclomine, placebo and combinations)

• Overall effectiveness (78% versus 57%), nausea (75% versus 52%), but not vomiting (73% versus 66%) when physician evaluated.

• Patients rated doxylamine/B6 better on nausea and vomiting.

• Drowsiness: 5.6% versus 3%, number need to harm=38.• Limitations: no demographics, high attrition (only 66% completed study), questionable data integrity (included potentially falsified data), possible selective reporting, inadequate adverse event reporting.

PLoS One. 2017;12(1):e0167609.

B6 Alone

• 4 Systematic reviews.1‐4

• Vit B6 “difficult to interpret”. Sometimes it was active intervention, sometimes control. Sometimes taken in addition to intervention.1

• 2 RCTs compared to placebo: no difference when combined.• One: Change VAS nausea score better with B6: 2.9 vs 2 and less vomiting (1.2 vs

0.65, P=0.055).• Other: severe nausea better with B6: 4.3 vs 1.8 and less vomiting episodes

(OR=0.30, 0.10‐0.89).

• 1 RCT compared high dose (10 mg ) to low (1.28mg); high dose better (change on 1 on PUQE score)

• 1 RCT from Iran found dimenhydrinate better

• 1 RCT from Malaysia found no difference from mint tictacs (placebo)

• 8‐way: only improved nausea as per MD.

1Matthews CDSR, 2Festin BMJ Clin Evid, 3McParlin JAMA, 4O’Donnell HTA

Ginger• 7 Systematic Reviews of RCTs, no meta‐analysis (example Cochrane: 12 efficacy outcomes, 8 positive). At best:

• Improves nausea and vomiting by ~4 points on a 40‐point scale compared to placebo

• Stop vomiting for 1 in 3 women at 6 days.1

• Similar efficacy to B6 (4 RCTs), ondansetron and doxylamine/pyridoxine (1 RCT each).

• Largest cohort (n~1000): no fetal harm2

• Smaller cohort (441 women): trend to more stillbirths (2.7% vs 0.3%) and major malformations (3.3% vs0.7%).3 1CDSR 2014;3:CD007575.

2Eur J Clin Pharmacol. 2013;69:269‐77.3J Obstet Gynaecol. 2015;35:125‐30.

Adrienne Lindblad

Ondansetron• Cleft palate (5 studies): 1 study found increased risk, 1 found trend to risk, 1 found prevented and 2 found nothing.

• Renal defects (2 studies): both found increased risk based on small numbers of cases (renal agenesis/dysplasia or obstructive defects).

• Heart defects (3 studies): 2 studies found increased risk, likely septal defects. Largest harm study is unpublished.

• 3 studies found no risks at all.• Including one using same databases as big heart defect study.

• Bottom‐Line: Ondansetron may pose a small risk, particularly of cardiac or renal defects, but the effects are inconsistent and the severity of these defects is unknown.

Future TFP. Obstet Gynecol. 2016 May;127(5):878‐83.

But does it work?• 3 systematic reviews on similar 3 studies, all vsmetoclopramide:

• 2 RCTs (n=70 and 160): no difference

• 1 RCT (n=83): inconsistent • Nausea:

• Days 1 and 7: no diff

• Day 3: ondan better 5.4 vs 6.0 on VAS, p=0.024

• Vomit: favours metoclopramide (by ~1 point)

• RCT compared to doxylamine/pyridoxine (n=36):• Ondansetron better for nausea, no difference vomiting.

Matthews CDSR. 2014;3:CD007575.BMJ Clin Evid. 2014;03:1405.O’Donnell. HTA 2016;20(74).

So What to Use?

• “There is a lack of high quality evidence to support any particular intervention”

• CDSR 2015;9:CD007575.

• This is NOT saying none of them work.

• Questions about ondasetron safety remain. • If there is a risk, it is small.

• Awaiting published research…

• Consider cost, availability, tolerability.

Serious Shortage of Reliable Info & Cardiac Malformations• 1 new cohort and 9 systematic reviews.1‐10

• 5 suggest effect is important.• Including one sponsored by industry.4

• 5 suggest the effect is not important1,5,6,8,10

• 4 have ties to industry1,5,6,8

• Other only included 4 studies10

1J Clin Psychiatry 2013;74(4):e293‐e308. 2Aust N Z J Psychiatry 2013 47:1002 3Daru. 2012 Nov 1;20(1):75. 4Birth Defects Res A Clin MolTeratol. 2010 Mar;88(3):159‐70 5J Obstet Gynaecol Can. 2008 Aug;30(8):696‐701 Clin Ther. 2007 May;29(5):918‐26.7PLoS One 2016;11(12):00165122. 8J Obstet Gynaecol Can. 2013;35(4):362‐9. Br J Clin Pharmacol. 2015;81(4):589‐604. 10J Am Heart Assoc. 2015;4:e001681.

Are women with depression at higher risk?• Cohort 949,504 women, 6.8% antidepressants 1st

trimester. Association with cardiac defects attenuated with increasing adjustment for confounding:

• Unadjusted: RR 1.25 (1.13 to 1.38), NNT = 558

• Restricted to depression: RR 1.12 (1.00 to 1.26)

• Fully adjusted & depression: RR 1.06 (0.93 to 1.22)

N Engl J Med. 2014 Jun 19;370(25):2397-407.

Does pregnancy have a protective effect on depressive relapse?

1) Cohort 201 high‐risk women. Depression relapse with antidepressant discontinuation proximate to conception1: • 68% vs 26% NNT = 3 (p<0.0001)

2) Cohort 778 women with hx of depression in past 5 years: no difference if on SSRI or not.2

1) JAMA. 2006 Feb 1;295(5):499-507. 2) Epidemiology. 2011 Nov;22(6):848-54

Adrienne Lindblad

Fish Oil and Atopy in Offspring• Cochrane Systematic Review: 8 RCTs, 3366 pregnant women.

• Mostly, 400‐4500mg Fish Oil OD, start gestation week 20‐30. • 76 meta‐analyses: 6 significant, with 4 based on ≥2 RCTs, at 1‐3 yrs.

• Any allergy: RRR 34%, NNT=23 & Eczema: RRR 39%, NNT=23• Plus skin prick tests for eggs and any allergen

• 6 individual RCTs: Inconsistent• 695 x6 yrs:5 Persistent wheeze/asthma, RRR 31%, NNT 15.

• Nothing else positive! • 706 children x3 years:6,7 Non‐significant reduction in many outcomes,

• Example: Any allergic disease with sensitization: RR 0.78 (0.58‐1.06)• Rest trickier: E.g. In 533, fish oil better than olive but same as nothing!

• Bottom‐Line: Fish oil in pregnancy is likely ineffective at preventing allergic disease in offspring as decreases in either eczema, food allergies or asthma in one study are generally not found in others and any positive effects seem to wane over time. Enthusiastic mothers could try fish oil supplements from ~20th week of gestation to delivery to prevent allergic disease in, at best, one in ~20 children.

N Engl J Med 2016;375:2530‐9. J Allergy Clin Immunol 2003; 112: 1178‐84.; ActaPaediatr2009;98:1461‐7.Allergy 2013; 68: 1370‐6. J Allergy Clin Immunol. 2017;139(1):104‐111

Summary• There is limited evidence that any drug for nausea/vomiting of pregnancy is better than another. Selection depends on cost, tolerability, availability.

• SSRIs: data inconsistent, much of the safety data potentially biased. If real, the risk of cardiac malformations low (NNH~200).

• Omega‐3s: unlikely to have much benefit in preventing atopy, might work for ~1 in 20 women.

Adrienne Lindblad

Alan Cassels, CD, MPA, Victoria, BC, Canada

Adapted from presenta.on at the Preven.ng Overdiagnosis Conference,

by Dr. Jessica O=e and Alan Cassels, Barcelona, 2016

Putting our “best foot forward” by doing the right thing.

Around the world with Choosing Wisely…

Faculty/Presenter Disclosure •  Faculty/Presenter: Alan Cassels

•  Rela1onships with commercial interests: –  Grants/Research Support: None –  Speakers Bureau/Honoraria: None –  Consul1ng Fees: Department of Orthopedics and Traumatology,

University of Helsinki; HealthNewsReview.org, University of Minnesota.

–  Other: Book royal,es: Agio Publishing; Greystone Publishing

CFPC CoI Templates: Slide 1

Disclosure of Commercial Support •  Poten1al for conflict(s) of interest:

–  Alan Cassels has received (or will receive) funding from the Department of Department of Orthopedics and Traumatology University of Helsinki which runs a campaign to prevent the overdiagnosis of osteoporosis.

–  Alan Cassels publishes ar.cles and blogs on overdiagnosis in a variety of medical journals and magazines.


Mi.ga.ng Poten.al Bias •  I have no commercial interest (shares, research consultancies,

etc) and am not dependent on the success or failure of Choosing Wisely Canada.


Learning Outcome Objec.ve Slide Provide at least one learning objec.ve. I expect a=endees to my lecture will learn something about the existence of worldwide movements to prevent overdiagnosis and realize that there the health systems of many countries around the world have embraced the concept of Choosing Wisely.

28th Annual Best Science Medicine Course: Slide 4

Alan Cassels

Objectives•  Discuss what is happening around the world in attempts to

prevent overdiagnosis.

•  Show the different flavours of “Choosing Wisely”-type initiatives around the world.

•  Discuss why this matters

Many ways to name “The Problem”

•  Overuse •  Overdiagnosis •  Overtes.ng •  Overtreatment •  Medicaliza.on •  Disease-‐mongering •  Iatrogenesis •  Making sick from well •  Too much medicine •  Inappropriateness

•  Iatrogenesis •  Overu.liza.on •  False posi.ves •  Misdiagnosis •  Overdetec.on •  Fu.lity •  Waste •  Pseudodisease •  Incidentalomas •  etc.

“Appropriateness is a complex, fuzzy issue that defines care that is effective (based on

valid evidence), efficient (cost-effective), and consistent with the ethical principles

and preferences of relevant individuals, communities or society.”

– WHO Report, 2000

EBM triad, -ish

UNITED STATES of AMERICA

CANADA

ALASKA (USA)

MEXICO

COLOMBIA

VENEZUELA

BRAZIL PERU

BOLIVIA

HONDURAS NICARAGUA

ECUADOR

GUYANA

SURINAME FRENCH GUIANA

COSTA RICA PANAMA

GUATEMALA

CUBA

PARAGUAY

ARGENTINA

URUGUAY CHILE

GREENLAND

ICELAND

UK IRELAND

NORWAY

SWEDEN FINLAND

DENMARK ESTONIA LATVIA

LITHUANIA

POLAND BELARUS GERMANY

CZECH R

NETHERLANDS BELGIUM

FRANCE

SPAIN PORTUGAL

SWITZ. AUSTRIA

SLOVAKIA HUNGARY

ROMANIA

BULGARIA ITALY

UKRAINE

TURKEY GREECE

SYRIA IRAQ

SAUDI ARABIA

YEMEN

OMAN

UAE

EGYPT LIBYA ALGERIA

MOROCCO TUNISIA

WESTERN SAHARA

MAURITANIA MALI NIGER

CHAD SUDAN

ETHIOPIA

SOMALIA UGANDA

SENEGAL

GUINEA

LIBERIA COTE D’IVOIRE

BURKINA

GHANA NIGERIA

CAMEROON

CENTRAL AFRICAN REPUBLIC

GABON CONGO DEMOCRATIC REPUBLIC OF

CONGO

KENYA

TANZANIA

ANGOLA ZAMBIA

MO

ZAM

BIQUE

NAMIBIA BOTSWANA

ZIMBABWE

REPUBLIC OF SOUTH

AFRICA

MADAGASCAR

RUSSIAN FEDERATION

KAZAKHSTAN

GEORGIA

IRAN

UZBEKISTAN TURKMENISTAN

AFGHANISTAN

KYRGYZSTAN

TAHKISTAN

PAKISTAN

INDIA

CHINA

NEPAL

MYANMAR

THAILAND

SRI LANKA

MONGOLIA

NORTH KOREA

SOUTH KOREA

JAPAN

TAIWAN

CAMBODIA

LAOS VIETNAM

PHILIPPINES

MALAYSIA

INDONESIA PAPUA NEW GUINEA

AUSTRALIA

NEW ZEALAND

Quaternary Prevention

action taken to identify patients at risk of overmedicalisation, to protect them from new medical invasion, and to suggest to them interventions which are

ethically acceptable

ISRAEL

Alan Cassels


CANADA

ALASKA (USA)

MEXICO

COLOMBIA

VENEZUELA

BRAZIL PERU

BOLIVIA

HONDURAS NICARAGUA

ECUADOR

GUYANA


COSTA RICA PANAMA

GUATEMALA

CUBA

PARAGUAY

ARGENTINA

URUGUAY CHILE

GREENLAND

ICELAND

UK IRELAND

NORWAY

SWEDEN FINLAND


LITHUANIA


CZECH R

NETHERLANDS BELGIUM

FRANCE

SPAIN PORTUGAL

SWITZ. AUSTRIA

SLOVAKIA HUNGARY

ROMANIA

BULGARIA ITALY

UKRAINE

TURKEY GREECE

SYRIA IRAQ

SAUDI ARABIA

YEMEN

OMAN

UAE

EGYPT LIBYA ALGERIA

MOROCCO TUNISIA

WESTERN SAHARA


CHAD SUDAN

ETHIOPIA

SOMALIA UGANDA

SENEGAL

GUINEA


BURKINA

GHANA NIGERIA

CAMEROON



CONGO

KENYA

TANZANIA

ANGOLA ZAMBIA

MO

ZAM

BIQUE

NAMIBIA BOTSWANA

ZIMBABWE

REPUBLIC OF SOUTH

AFRICA

MADAGASCAR

RUSSIAN FEDERATION

KAZAKHSTAN

GEORGIA

IRAN


AFGHANISTAN

KYRGYZSTAN

TAHKISTAN

PAKISTAN

INDIA

CHINA

NEPAL

MYANMAR

THAILAND

SRI LANKA

MONGOLIA

NORTH KOREA

SOUTH KOREA

JAPAN

TAIWAN

CAMBODIA

LAOS VIETNAM

PHILIPPINES

MALAYSIA


AUSTRALIA

NEW ZEALAND

Slow Medicine

aims to create a return to medicine that is sober (avoiding excess), respectful, and fair. A slower paced approach to care would have patients experiencing a gentler,

less burdensome approach to achieving health and good living

ISRAEL


CANADA

ALASKA (USA)

MEXICO

COLOMBIA

VENEZUELA

BRAZIL PERU

BOLIVIA

HONDURAS NICARAGUA

ECUADOR

GUYANA


COSTA RICA PANAMA

GUATEMALA

CUBA

PARAGUAY

ARGENTINA

URUGUAY CHILE

GREENLAND

ICELAND

UK IRELAND

NORWAY

SWEDEN FINLAND


LITHUANIA


CZECH R

NETHERLANDS BELGIUM

FRANCE

SPAIN PORTUGAL

SWITZ. AUSTRIA

SLOVAKIA HUNGARY

ROMANIA

BULGARIA ITALY

UKRAINE

TURKEY GREECE

SYRIA IRAQ

SAUDI ARABIA

YEMEN

OMAN

UAE

EGYPT LIBYA ALGERIA

MOROCCO TUNISIA

WESTERN SAHARA


CHAD SUDAN

ETHIOPIA

SOMALIA UGANDA

SENEGAL

GUINEA


BURKINA

GHANA NIGERIA

CAMEROON



CONGO

KENYA

TANZANIA

ANGOLA ZAMBIA

MO

ZAM

BIQUE

NAMIBIA BOTSWANA

ZIMBABWE

REPUBLIC OF SOUTH

AFRICA

MADAGASCAR

RUSSIAN FEDERATION

KAZAKHSTAN

GEORGIA

IRAN


AFGHANISTAN

KYRGYZSTAN

TAHKISTAN

PAKISTAN

INDIA

CHINA

NEPAL

MYANMAR

THAILAND

SRI LANKA

MONGOLIA

NORTH KOREA

SOUTH KOREA

JAPAN

TAIWAN

CAMBODIA

LAOS VIETNAM

PHILIPPINES

MALAYSIA


AUSTRALIA

NEW ZEALAND

Choosing Wisely

a campaign to help clinicians and patients engage in conversations about unnecessary tests, treatments and procedures

ISRAEL

Spain, Catalonia Portugal

Germany

l  The German Society of Geriatrics (DGG), German College of General Practitioners and Family Physicians (DEGAM) developing guidelines

l  “A clear, transparent, structured and evidence-based approach may help avoid some of the methodological weaknesses to be found in the development of the U.S. recommendations. Whereas the U.S. campaign only addresses overuse, the German campaign will also address underuse and misuse.”

-  Gogol, M. & Siebenhofer, A. Wien Med Wochenschr (2016) 166: 155. doi:10.1007/s10354-015-0424-z

Italy

Nardi R, Berti F, Fabbri L, et al. of the FADOI and Friends in the Appropriate decision making Project Group (FFA-PG) in hospital Internal Medicine wards. Toward a sustainable and wise healthcare approach: potential contributions from hospital Internal Medicine Departments to reducing inappropriate medical spending. Ital J Med 2013:7:65-81.

Alan Cassels

The Netherlands

•  Four parallel initiatives: – “Wise choices” – promoting shared decision-making with

patients – evaluating quality and efficiency of care –  identifying variations in practice

Switzerland

The Good Stewardship Working Group

En médecine, moins peut aussi être plus

Sweden “Wise List' by the regional Drug and Therapeutics Committee in Stockholm

Gustaffson et al. The 'wise list'- a comprehensive concept to select, communicate and achieve adherence to recommendations of essential drugs in ambulatory care in Stockholm. Basic Clin Pharmacol Toxicol. 2011 Apr;108(4):224-33.

Finland

France UK

Alan Cassels

UK factors? Strong organiza.ons – BMJ, NICE, Oxford CEBM, Royal College, etc

Israel•  Choosing Wisely •  Preventing Overdiagnosis

Russia Taiwan

Japan South Korea

•  Physicians in South Korea led a public campaign on the issue of overdiagnosis of thyroid cancer. Under the government sponsored national screening programme, diagnosis of various cancers, in particular thyroid cancer, has increased dramatically, making it the most common cancer. Mortality from thyroid cancer has remained steady, yet virtually all people with this diagnosis are treated. The physicians’ campaign resulted in the National Cancer Centre recommending against routine thyroid cancer screening in asymptomatic people

- Hyeong Sik A, Hyun Jung K, Welch HG. Korea’s thyroid-cancer “epidemic”: screening and overdiagnosis. N Engl J Med2014;371:1765-7.

The Coalition of Doctors to Prevent Over-diagnosis of Thyroid Cancer

Alan Cassels

Australia

CATALYST, 4 CORNERS

India

•  Society for Less Investigative Medicine (SLIM) - Travasso C. Indian cardiologists plan campaign to reduce unnecessary investigations. BMJ2014;349:g4740

India

?Factor: Strong academic tradi.ons – Impera,ve to reach diagnosis

“Young doctors identified how throughout medical training they were taught, almost compelled, to reach “a diagnosis” and to offer several provisional diagnoses to be confirmed through a battery of investigations. Clinching a diagnosis got you acknowledgment from professors and peers and helped you crack the exams, sending a signal that a good clinician was one who could diagnose with precision. . . This culture of investigative medicine has boosted the growth of diagnostic services, the fastest growing segment of India’s healthcare industry. . .” – Jain, Anita. Too much medicine is not just a problem of rich countries BMJ 2015; 350 :h1095

Africa?•  Research from Asian and African countries where malaria is

endemic shows that doctors tend to start presump.ve treatment for malaria in pa.ents with fever, even if laboratory test results are nega.ve, resul.ng in overtreatment.

•  Overprescrip.on of an.malarials has led to drug resistance and also missed treatment for serious non-‐malarial infec.ons.

-‐ Jain Anita. Too much medicine is not just a problem of rich countries BMJ 2015; 350 :h1095

Brazil Other South America•  QP Uruguay •  Quaternary prevention Argentina

Alan Cassels

USA

Promoting Good Stewardship in Medicine

Radiologist Selfie

America Choosing Wisely•  In America, over 100 national, regional and state medical organizations

have released more than 70 lists of tests and procedures they say are overused. Health organizations across the country have used these recommendations.

•  Notably, Cedars-Sinai Medical Center in Los Angeles slashed unnecessary health care costs by more than $4 million in one year by programming over 100 Choosing Wisely recommendations into its electronic medical records (EMR) system. For example, the system reminds physicians not to prescribe benzodiazepines for insomnia in patients over 65, because these drugs increase the risk of falls. As a result, prescribing of benzodiazepines to older patients dropped 30%.

•  Since 2013, the ABIM (American Board of Internal Medicine Foundation) has also awarded $2.5 million in grants for projects to raise public and physician awareness about Choosing Wisely.

•  - Vogel L. Choosing wisely around the world. Canadian Medical Association.Journal. 2015;187(11):E341-E342.

Canada

…whatever you want to call it…

Lynn Nyman, RN (with Dr Malvinder Parmar)

Key References1.  Vogel L. Choosing wisely around the world. Canadian

Medical Association.Journal. 2015;187(11):E341-E342.

2.  Levinson W, Kallewaard M, Bhatia RS, et al. “Choosing Wisely”: a growing international campaign. BMJ Qual Saf 2015;24:167–74.

3.  Frey, B. Overtreatment in threshold and developed countries. Arch Dis Child 2008;93:260-263.

4.  Carter S M, Rogers W, Heath I, Degeling C, Doust J, Barratt A et al. The challenge of overdiagnosis begins with its definition. BMJ 2015;350:h869

Alan Cassels

How to contact me

•  Alan Cassels Victoria, BC. •  [email protected] •  Twi=er: @AKECassels •  250 361 3120

Alan Cassels

Tina Korownyk and Mike Allan PEER (Patient Experience Evidence Research),

Alberta College of Family Physicians & University of Alberta

“The short and the long of it” Top 10 studies that you need to know about


• Faculty/Presenter: Mike Allan, Tina Korownyk

• Where we get Personal $: U of A, Alberta Health

• Where we get Grant/ Program $: Alberta College of Family Physicians, Other Colleges of Family Physicians, Toward Optimized Practice, Other non‐profit organizer

• Relationships with commercial interests:– Grants/Research Support: Not applicable

– Speakers Bureau/Honoraria: Not applicable

– Consulting Fees: Not applicable

– Other: None

Learning Outcome Objective

• Review Studies from the last year that – Have received the greatest attention and need consideration regarding

application to practice. OR

– That did not receive as much attention but may have a large impact on practice.

28th Annual Best Science Medicine Course

Delayed Antibiotic• TFP #53 (May 12 2015): delayed scripts may slightly worsen

satisfaction/or symptoms but reduce Abx use ~60%

• RCT of 405 adults (pharyngitis, bronchitis, rhinosinusitis):

– Immediate Abx, Delayed (give pt), Delayed (at clinic), No Abx

JAMA Intern Med. 2016;176(1):21‐29.

• Same satisfaction, but delayed felt Abx less important (19% vs 8%)• Absenteeism: ↑ immediate and no Abx ~35‐40% vs ~23%

• Bottom‐Line: Nothing ↓Antibiotic use more than Delayed Scripts.

Immediate Abx

Delay (Rx to pt)

Delay (collect later)

No Script

Duration Mod Sx 4.7 days 6.0 days 5.2 days 6.5 days

Antibiotic Use 91% 33% 23% 12%

TK

Testosterone in Older Men

• TFP #112: for sexual function SMD 0.65‐1.3• 3 overlapping RCTs (sexual, physical, vitality): 790 pts, age ~73

– Enroll if serum testosterone <9.5 nmol/L (275ng/dL) and age ≥65. – Androgel 1%, start with 5gm, titrate to normalize testosterone

• Sexual Outcome: ~5% better; e.g. PDQ‐Q4 (0‐12, higher better, mean 1.5): 0.6 better

• Physical Function: ¾ not statistically significant in Physical trial : – All patients: Increase ≥50m 6‐minute 21% vs 13%

• Vitality Outcome: ≤2.5% better, e.g. FACIT‐Fatigue score (0‐52, higher less fatigue) 1.3

• Bottom‐Line: Testosterone is “effective” but that effect is really very small: Sexual function improves 5‐9% while with strength and vitality changes are tiny (≤3%).

N Engl J Med 2016;374:611‐24.

MA

Sodium and CVD/mortality

• Pooled data from 2 RCTs and 2 cohorts.– 133 118 (63 559 hypertension, 69 559 not), median age 55 years (IQR 45–63), followed x4∙2 years.

• Outcome: 1 gm sodium increases SBP 2.1mmHg in hypertensives and 1.2 in normotensives.

– If CKD (GFR 20‐70), lowest risk 2.9‐3.6 g/d.2

• Bottom‐line: Sodium is intake a U shaped curve, particularly in hypertensive patients.

Lancet. 2016 Jul 30;388(10043):465‐75. 2) JAMA. 2016;315(20):2200‐2210.

<3 g/d 3‐4 g/d 4‐5 g/d 5‐6 g/d 6‐7 g/d ≥7 g/d

Not Hypertensive 1.26 1.05 1 0.99 0.92 0.90

Hypertensive 1.34 1.16 1 0.99 1.12 1.26

TK

Tina Korownyk and Mike Allan

Wet vs Dry Skin for Eczema

• RCT: 47 children (mean age 3.1 yrs). uncontrolled eczema.

• Topical Steroid (triamcinalone 0.1%/hydrocortisone 2.5%) ointment BID, randomized to OD (evening) wet skin and apply vs dry. x2 weeks. - Percent Improvement: 84.8% vs 81.4%, No statistical Difference

- Pruritis score, sleep score, overall impact score: No diff

• Harms: - Folliculitis (13% and 21%) noted by derm (not patients)

- 9 had a.m. cortisol: 8 normal & one 4.75 ug/dL (normal is 5)

• Bottom‐Line: The evidence‐base for wetting skin before application is from observational studies. This is the best research so far and indicates that wetting the skin is not required.

7J Am Acad Dermatol 2016;75:306‐11.

MA

Sleep Apnea, CPAP & CVD

• RCT: 2717 pts (age 61, 81% male, 100% CVD), mean 28 desats (of ≥4%) /hr. CPAP vs no CPAP x 3.7 yrs.

• Outcome: mean CPAP use 3.3 h/night (42% >4h)– CVD: 17% vs 15.4% (no CPAP)– Death & CVD death: No diff– Stat sign: Epworth 2.5 (out of 24) better, QoL 1‐2% better, – Not sign: MVA 3% vs 3.5%, injurious accidents 7.4% vs8.8% (p=0.06),

• Bottom‐Line: CPAP nothing for hard outcomes, works for sleepiness and other changes are slight (1‐2%) or nothing.

McEvoy N Engl J Med 2016; 375:919‐931

TK

Changing Dietary Fats to Live Longer

• RCT: Minnesota Coronary Experiment (MCE) 1968‐73, follow‐up 3 yrs, 2355 pts, age 52, 53% male, – vegetable oil (n‐6 linoleic acid via corn, replace saturated fat

• Outcome: Cholesterol down 14% (0.8 mmol/L) vs 1%

– Recovered survival analysis: No effect (if anything, trend to harm, particularly age ≥65)

• Partial data with autopsy (on MI): 41% diet vs 22% control

– Meta‐analysis (5 RCTs, 10,808 pts): actual diet (not advice)• CHD death = hazard ratio 1.13 (0.83 to 1.54)

• Bottom‐Line: No RCT support dietary modification of fats intake to improve CVD or death.

Ramsden. BMJ 2016;353:i1246

MA

Liraglutide (GLP-1) and CVD

• RCT liraglutide 1.8mg vs placebo, 9340 pts, x3.8 yrs– 64% male, age 64, DM 13 yrs, A1c 8.7%, CVD 82%.

• Outcome (A1c ~1% diff, but 0.4% at end; ~7.7% vs 8.1%)– CVD: HR 0.87 (0.78-0.97), 14.9% vs 13%, NNT=53.

• Death: 9.6% vs 8.2% (NNT 72)

• Microvascular: NNT 67 (via nephropathy), retinopathy +0.3%

• Note: weight 2.3 kg better, severe Hypo 0.9% less(!)

– Total neoplasm (10.1% vs 9% ns), pancreatic Ca (0.3 vs 0.1%, p=0.06), gall bladder disease (NNH 82); N/V/D (NNH 200-82 each)

• Bottom-Line: Works! NNT ~50 in high risk diabetics. Not target based. (note: lixisenatide RCT found no effect)

1. Marso SP. N Engl J Med 2016; 375:311-322 2. NEJM 2015;373:2247-57.

TK

BMJ. 2017 Feb 15;356:i6583.

1st Meta‐analysis Odds Ratio0.88 (0.81‐0.96)

53%, p=0.001

Redo Meta as Relative Risk0.96 (0.91‐1.00)

If real, any URTI 40.3% vs 42.2%NNT 53

Mongolian 10 y.o., Any RTI (Vit D lvl 17.5)

USA Healthy 59 y.o, any RTI

Afghanistan, poor, 0‐3 y.o. pneumonia

New ZealandHealthy 47 y.o.Colds

Afghanistan, poor, 0‐1 y.o. pneumonia

Who Might Vit D be effective For: Daily low (~800 IU) doses in people with Vitamin D level <25 nmol/L.

Systematic Review: 25 RCTs (11,321 patients)‐ 50% ≤1 y.o. and 62% levels not tested Essential Tremor: A Real Solution?

• RCT: 76 patients, age 71, 68% male– focused ultrasound thalamotomy vs sham

– Mean hand‐tremor ~18 (out of 32)

• Outcome (at 3 months): (in contralateral hand)– No change with sham treatment

• Mean 47% improvement at 3 months, 40% at 12 months

– CRST (total tremor): improved 40% from baseline• Quality of life, etc: all ++ better

– Harms: 38% paresthesia/numbness, 36% gait disturbance• By 12 months: 14% and 9% respectively.

• Bottom‐Line: Promising for serious hand tremor.

N Engl J Med 2016;375:730‐9.

TK


Big Doses of Vitamin D: Is more better?Mega‐Dose: 4 +ve of 4 RCTs for Harm.

• Fracture: 2 +ve of 4 RCTs, NNT none to 32 x3 yrs

• Falls: 3 +ve of 4 RCTs, NNT none to 6 x1 yr

- Certain individuals particularly susceptible (more fallers but for those that fall, lots more falls). Incident Rate Ratio 2.33

- Mean number of falls 0.94 versus 1.47 in one year

Ginde 2016 Bischoff 2016 Sanders 2010 Smith 2007

Dose 100,000 IU/month oral

60,000 IU/month oral

500,000 IU/year oral

300,000IU/year IM

shot

Levels ~ 83 nmol/L ~ 100 nmol/L 120 ‐ 75 nmol/L Not given

J Gen Intern Med. 2016;31:780‐91. JAMA Intern Med. 2016;176:175‐83. Ginde J Am Geriatr Soc 2016.

• Bottom‐Line: Do not give big doses of Vitamin D, particularly to the elderly.


“Tzx? ã|à{ {|á áàxtÄ|Çz áàxÑá? [tà{ vÄtãxw Åx |Ç {|á vÄâàv{AÊ

Top things we screw up with the elderly.

Rita McCracken, MD, CCFP(COE)


• Faculty/Presenter: [Rita McCracken]

• Relationships with commercial interests:– Grants/Research Support: n/a

– Speakers Bureau/Honoraria: n/a

– Consulting Fees: n/a

– Other: n/a

Disclosure of Commercial Support

• This program has NOT received ANY financial support.

• This program has NOT received ANY in‐kind support.

• Potential for conflict(s) of interest:

– n/a

– n/a

Mitigating Potential Bias

• I will provide a published source to support every statement that I make.

• I welcome feedback if bias is noted by any audience member. (please be specific about what you heard me say and why you think it is biased).


1. Describe quality of evidence that informs physician ordered fluid consistency diet changes for frail elders.

2. Consider this evidence and how it might apply to shared decision making, with frail elders and their carers, about diet modifications.

28th Annual Best Science Medicine Course

Is food related to quality of life?

Barnhart et al. BMC Geriatrics (2016) 16:28, PMID: 26813788

Rita McCracken

MD’s, likely part of the problem…

“In conclusion, we found that VA NH residents with diabetes were substantially burdened by […] dietary restrictions […]. […] physicians appeared to underestimate how burdensome dietary restrictions are for NH residents.

But is “Quality of Life”

just a nice to have?

Quality of Life

Nice to have?

Or, linked to mortality?

JAGS 64:831–837, 2016, PMID: 27100579

What did they measure?

• over seven years• demographic variables for Frail older women (N = 11,070; average age 72.6, range

65–82).– (race and ethnicity (white, nonwhite); – highest level of education (≤high school; >high school)); – marital status (currently married or partnered; not married);

• Frailty was defined using the modified Fried criteria. • smoking status (nonsmoker; current smoker); • Medical Hx, Incl: history of cancer (excluding nonmelanoma skin cancer), diabetes

mellitus, cardiovascular disease, hypertension, and arthritis. • diet, • medication regimen, • self‐rated health, • somatic and • depressive symptoms, • Quality of Life

JAGS 64:831–837, 2016, PMID: 27100579

Impacts on Survival

1. Not having cancer, better

2. Higher Weight, better – (consistent with JAMA. 2013 Jan 2;309(1):71‐82.)

3. Think of yourself as healthy (independent of what health measures say), better

4. Alcohol, equivocal

5. Quality of Life higher, betterJAGS 64:831–837, 2016, PMID: 27100579

2 new systematic reviews to describe“effectiveness of interventions to directly support food and drink intake in people with dementia”

Abdelhamid et al. BMC Geriatrics (2016) 16:26.PMID: 26801619

Cochrane Database Syst Rev PMID: 27996085

Rita McCracken

What the reviews say

• “While we found no definitive evidence on effectiveness, or lack of effectiveness, of specific interventions, studies were small and short term. […] The need remains for high quality trials tailored for people with progressive cognitive impairment and their carers assessing robust and relevant outcomes.”

Surely (Shirley?), there must be GOOD evidence about thickened fluids?(better than the diabetes diets, … right?)

Aging Dis. 2015 Feb; 6(1): 27–37. PMCID: PMC4306471

Risk Factors Associated with Aspiration Pneumonia

For your patient:What is potentially modifiable?

What does s/he want?

1 RCT (Robbins, 2008, Arch Int Med)

Ann Intern Med. 2008 April 1; 148(7): 509–518. PMID: 18378947

“We compared 2 common but untested interventions to prevent pneumonia—chin‐down posture and thickened liquids—in persons with dementia or Parkinson disease (or both conditions) who had a known tendency to aspirate liquid.”

Survival Curve Interpretation Cheat Sheet:…If the lines cross, there is no difference between the things being compared.


“No definitive conclusions about the superiority of any of the tested interventions can be made. The 3‐month cumulative incidence of pneumonia was much lower than expected in this frail elderly population.”


Rita McCracken

Conclusions:

“Our findings should prompt clinicians to question the practice of recommending very thick liquids (in this case, 3000 centipoise) without first evaluating all possible intervention options and considering the relative cost burden to the patient and care providers, not just in terms of dollars but also quality of life.”(emphasis added)

Bottom line:• Eating and drinking become more difficult as dementia and frailty progress. (Aging Dis. 2015 Feb; 6(1): 27–37. PMCID: PMC4306471)

• Eating and drinking are an important part of most people’s lives and can have an effect on quality of life. (#ThickenedLiquidChallenge & Barnhart et al. BMC Geriatrics (2016) 16:28. PMID: 26813788)

• Rates of aspiration pneumonia do not appear to be decreased when comparing: chin tuck, nectar or honey thick fluids. (Ann Intern Med. 2008 April 1; 148(7): 509–518. PMID: 18378947 )

• Other diet interventions are also inconclusive in terms of effect on morbidity, mortality and quality of life. (2 systematic reviews)

Talking about eating at risk.

• “Your mom/dad’s dementia and increasing frailty increase the chance that s/he might choke on her food. This is an expected part of the progression of dementia.”

• “Unfortunately, we have no good evidence about ways to reduce that risk. Some people recommend feeding in a certain position, or thickening fluids, but the available research does not find a reduction in someone getting pneumonia between those methods.”

• “In my experience, many patients do not like the taste or texture of thickened fluids or pureed diets and get more pleasure and nourishment from foods they recognize and prefer.”

• “We don’t know how much more time your mom/dad has left with us, but it is reasonable to assume that it is less than if they did not have dementia. We can make choices that help increase the quality of her/his life each day that s/he is here. Or, we could focus on keeping her/him alive as long as possible.

– “What do you think your mom or dad would want?”

• “Do you have any worries or questions for me about her/his risk of choking and eating and drinking?”

– “feel free to talk this over with the rest of your family and come back to me with any questions or ideas”.

Rita McCracken

Guidelines - Neither Rhyme Nor reason

James McCormack, BSc(Pharm), PharmD Professor, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC

1) Disclosure of Commercial SupportNeither this program nor the presenter has received financial support from any organization or company.

2) Mitigating Potential BiasAll recommendations and information presented are based on the best-available evidence we could find. Typically this includes meta-analyses, systematic reviews and RCTs. In addition, we don’t care what the results are, but rather we care that people know about the results.

3) ObjectivesTo be able to take the best available evidence for common conditions in primary care and incorporate this information into shared-decision making with patients.

The Institute of Medicine definition:

"…statements that include recommendations, intended to optimize

patient care, that are informed by a systematic review of evidence and an assessment of the benefits and harms

of alternative care options”

What is a Clinical Practice Guideline (CPG)?The Number of Guidelines Diseases/conditions - 2,983 Treatments/interventions - 7,364

~10,000 guidelines ~10 pages each? ~100,000 pages 500 pages ~ 2 inches 400 inches ~ 33 feet ~10 meters Highest pole vaulter ~ 20 feet ~ 6 meters War and Peace is ~1500 pages ~ 70 copies

10 meters

James McCormack

“medical history is littered with clinical practice guidelines that have been fatally incorrect”

“the physician's ability to keep up with the medical literature erodes with each year's burden”

“costly and unexplained variability in medical practice” “growing demand from patients for greater

participation in medical decisions”

J Gen Intern Med 1997;12(Suppl 2):S25–S33

1997 - THE REASONS FOR INTEREST IN QUALITY CLINICAL PRACTICE GUIDELINES

“Unfortunately, depending on how their reliability is measured, up to 50% of guidelines can be considered untrustworthy. This carries serious consequences for patients’ safety, resource use and health economics burden.”

EBM 2017;22:1-3

“guideline reliability is largely over-stated, and guidelines still suffer methodological flaws, limited panel composition and conflicts of interests, making their conclusions often untrustworthy. Even when evidence-based methodology is claimed, it is often not fully adopted and the ‘evidence-based quality mark’ gets misappropriated by vested interests”

EBM 2017;22:1-3

“Furthermore, no official, publicly accountable, reliable, independent and unconflicted rating agency of published guidelines exists.”

EBM 2017;22:1-3

James McCormack

Where to find CPGs

1. Canadian Medical Association Infobase (Canada) - Clinical Practice Guidelines - www.cma.ca/cpgs

2. National Guideline Clearinghouse (USA) - www.guideline.gov

3. National Health Service Evidence (UK) - www.evidence.nhs.uk)

4. Clinical Practice Guidelines Portal (Australia) - www.clinicalguidelines.gov.au

5. Turning Research Into Practice (TRIP) - www.tripdatabase.com

6. PubMed - can limit a search to practice guideline

7. Just do a google search

How to assess CPGs “the most comprehensively validated appraisal tool is the

AGREE II instrument

PLoS ONE 8(12): e82915. doi:10.1371/journal.pone.0082915

James McCormack

Appraisal of Guidelines for Research and Evaluation (AGREE) II

DOMAIN 1. SCOPE AND PURPOSE

DOMAIN 2. STAKEHOLDER INVOLVEMENT

DOMAIN 3. RIGOUR OF DEVELOPMENT

DOMAIN 4. CLARITY OF PRESENTATION

DOMAIN 5. APPLICABILITY

DOMAIN 6. EDITORIAL INDEPENDENCE

OVERALL GUIDELINE ASSESSMENT

How to use CPGs

1. Is the CPG trustworthy?

2. Is the CPG applicable to your patient?

3. Is the CPG setting similar to your practice?

4. Does the CPG reflect you or your patient’s values and preferences?

The Jekyll and Hyde problem with CPGs

James McCormack

“CPGs can undermine clinical growth by providing a tempting academic short-cut: memorizing clinical facts

rather than learning clinical principles”

Amer J Pharmaceutical Education 2015;79

“Rather than endeavor to design a map with an answer for every question, I believe

that it would be preferable to educate clinicians to handle clinical reality directly

and without filtered advice”

JAMA July 8 2009

“Bombarding students with guidelines for all scenarios … may seem more efficient in

the short-term but does little to enhance discriminatory skills and numbs the facility

for critical thinking.”

JAMA 2009;302:145

Spectrum of Decisions1.Immediate life-threatening issues or very “technical” work - surgery, dispensing etc - YES Guidelines, even policies, are likely very useful

2.Symptom treatment - SORT OF Each person is an experiment - need to know just what has the potential to work and the safety

3.Risk factor interventions - NO At least not what CPGs are now

James McCormack

“So rare that it’s a

super power”

Combine Evidence with Common Sense

SHHH. MY COMMON

SENSE IS TINGLING.

Common Sense“So rare that it’s a

superpower”

Guidelines

What the … guidelines aren’t based on

solid evidence?

Guideli

nes elines

How evidence-based

are CPGs?

Typically “evidence-based” guideline recommendationsare not based on “solid” evidence

EVIDENCE LEVEL Cardiology Infectious

disease Endocrinology

1 or Abased on RCTs 11% 14% 6%

3 or Cbased on opinion 48% 55% 35%

Qual Saf Health Care 2010;19:e58. doi:10.1136/qshc.2010.042077

Engaging the right people, quality of evidence appraisal, providing useful tools, and competing interests have not

improved in 14 years (1993-2007)

Top Score = 100%

James McCormack

Recent examples of Guideline Quality/Rigour AGREE II (Appraisal of Guidelines for Research and Evaluation)

is the instrument typically used - 207 guidelines

avg 55% - neuropathic pain - 16 CPGs - range 27%-88% - BMC Anesthesiology 2016;16:12

avg 30% - hypertension - 11 CPGS - range 8%-86% - PLoS ONE 2013 8(1): e53744

avg 32% - asthma - 18 CPGs - range 8%-64% - Chest 2013 144: 390-7

avg 48% - diabetes - 24 CPGs - range 0%-81% - PLoS ONE 2013 8(4): e58625

avg 20% - vancomycin - 12 CPGs - range 4%-73% - PLoS ONE 2013 9(6): e99044

avg 18% - hypertension (China) - 17 CPGs - range 1-36% - BMJ Open 2015;5:e008099

avg 8% - respiratory (China) - 109 CPGs - range 0%-27%- Chest 2015;148:759-766

August 2016

Endpoints - End Stage Renal Disease/dialysis, renal death, blindness or clinical neuropathy5 large trials, 8 meta-analyses, 2 follow-up trials31 estimates of outcomes

2 (6%) suggested benefit 29 (94%) suggested NO benefit

Endpoints - all-cause mortality, CV mortality, non-fatal MIs, stroke, amputations/PVD5 large trials, 10 meta-analyses, 5 follow-up trials78 estimates of outcomes

10 (13%) suggested benefit 64 (82%) suggested NO benefit 4 (5%) suggested harm

Circ Cardiovasc Qual Outcomes. 2016;9:00-00. DOI: 10.1161

Evidence since 1998 forTight glycemic control (A1c 6.5%-7%) vs less tight (A1c 7%-8.5%)

despite this, over the last 10 years - “practice guidelines and published statements offer a consistent and confident consensus, with 100% of the

guidelines and 77% to 100% of the statements in favor of tight glycemic control to prevent microvascular

complications”

Overall estimates of benefits and harms (micro and macro)

11% of estimates = a benefit 4% of estimates = harm

85% of estimates = no benefit

Circ Cardiovasc Qual Outcomes. 2016;9:00-00. DOI: 10.1161

James McCormack

Who writes/sponsors

guidelines?

176 PRIMARY CARE guidelines in the CMA database

CONTRIBUTORS54% non–family physician specialists 17% family physicians - 8% if industry sponsored 11% other clinicians 8% non-clinician scientists 6% nurses 3% pharmacists

Can Fam Physician 2015;61:52-8

69% of guidelines didn’t report conflicts of interest

Guideline sponsorship2009 - 2,300 guidelines in the National Guideline Clearinghouse

Guideline development

41% - medical speciality societies

22% - government agencies/nonprofit

17% - professional associations

9% - disease specific societies

4% - independent expert panels

http://www.ncbi.nlm.nih.gov/books/NBK22928/

at least 2/3 are being developed by groups with

a clear potential for important biases

BMJ 2011;343:d5621 doi: 10.1136/bmj.d5621

~50-80% of panel members on guidelines have financial COIs

BMJ;2013:346

James McCormack

How well do guidelines address patient values and

preference?

But I don’t want

to take a pill!

Of course you do,

I’m the expert!


197 PAGES - 90,000 WORDS99(0.1%) words - relevant to

patients’ values and preferences

5 Canadian Guidelines forblood pressure, cholesterol, glucose, and bone density

Looked for info onRisk estimation (magnitude)Impact of treatment on riskPotential harms (magnitude)

“The information presented in these documents is glucose-centric and not organized or presented in a way that could

be construed as supporting shared decision making”

Diabetes Care January 2015

113 PAGESTotal mention of values and preferences - 0.19% of the words“Practitioners are advised to consider patient preferences, values, and

clinical factors when determining how to best apply these recommendations at the bedside”

~11,800 words - 20 pages

“In the absence of Canadian data to determine the accuracy of risk calculations, avoid using absolute levels of risk to support treatment

decisions”

James McCormack

ResultsPatients Median

acceptable absolute % benefit threshold

% that would take a “safe” drug for 5 years

Absolute % benefit they felt they were getting from their drug

% who wanted to be told percent chance of benefit

If benefit over 5

years was < 5%

If benefit over 5 years was < 5% AND their MD

recommended it

Post MI patients

20 32 69 70 79On drugs 20 29 74 68 72No drugs

30 21 56 - 84Clin Med 2002;2:527-33

307 subjects using a written questionnaire and interview

53 residents, 8 fellows, 18 attending physicians

The mean degree of over-estimation compared to the Framingham estimate:

low-risk scenarios - 7.8 timesmedium-risk scenarios - 2.8 timeshigh-risk scenarios - 1.5 times

BMC Health Services Research 2003;3:13

Ability of clinicians to make an estimate of CHD risk

What is "High Risk"

% o

f re

spo

nd

ents

0

10

20

30

40

Chance of a heart attack in the next 5 years (%)1-3 4-5 6-10 11-20 21-30 31-40 41-50 51-75 76-100

CliniciansPatients

% “Many of the preferences expressed by the clinicians and lay people in this

study are at odds with recommendations in guidelines”

BMJ 2003;327:841

Qualitative study using semi-structured interviews

James McCormack

“A typical patient in our study required a 50% absolute fracture risk and

50% relative risk reduction (giving an absolute risk reduction of 25%) before considering long-term drug therapy”

Osteoporos Int 2012;23:2135–40

A prominent current guideline … recommends pharmacologic intervention at thresholds of 10- year risk of 20% for major osteoporotic fracture or 3% for hip fracture

125 (77%) of doctors would recommend treatment 24 (21%) of our patient cohort would consider treatment justified

Did NOT ask patients to consider side effects or drug cost, just the dosing regimen, in the decision

The Bottom Line Sep 2011

Even an authoritative CPG may NOT be found to be determinative of a standard of care.

It is prudent for physicians to be aware of authoritative clinical practice guidelines relevant to their practices. If a clinical decision may be perceived as being contrary to a recognized and accepted CPG, a physician, where appropriate, may consider the following steps: consult with a colleague or relevant specialist, discuss reasonable treatment options with the patient, and document the patient's consent for the chosen treatment.

If deviating from an established CPG, physicians should consider documenting the rationale for doing so, as well as any discussions with the patient about such variance.

Obviously inform you that CPG’s exist

We all need to discuss up front the limitations and issues of clinical practice guidelines

We need to know how to appraise and integrate the best available evidence

Admit we don't have answers for everything

We need to help you think for yourselves and use common-sense

Need to be allowed to make “mistakes”

It is totally OK to go “against” the guidelines

Education and Guidelines The Guideline Solution?What should guidelines contain?

Who should write them?

What should they not contain?

Are there examples of well-done guidelines?

James McCormack

Guidelines should provide ballpark estimates of what happens if

you DON’T treat/test/screen and if

you DO treat/test/screen

Guidelines would be awesome if they…

Were developed primarily by, and definitely for, the people that ultimately end up using them

Were a credible synopsis of the best available evidence presented in a way that clinicians could easily access and interpret

Allowed patient values and preferences to be taken into account


An Example of a Guideline that Promotes Discussion Rather than Treatment

James McCormack

Thanks for your questions and discussion.

Thanks for completing your course evaluations.

28th Annual Best Science Medicine Course · 2018. 5. 22. · Research glutamate and adenosine...

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Transcript of 28th Annual Best Science Medicine Course · 2018. 5. 22. · Research glutamate and adenosine...