Kliniske undersøgelsers hierarki Dirac kursus 4 b 30-3

Kliniske undersøgelsers hierarki
Dirac kursus 4 b
30-3-2005
Henrik E. Poulsen
Professor, Overlæge dr.med.
Klinisk Farmakologisk Afdeling Q7642
Rigshospitalet
Tel 3545 7671 henrikep@rh.dk
she
September 1999
http://www.themedweb.co.uk/didyouknow/
Zoneterapi
Vaginal zoneterapi
Skrevet af Camilla Kjems
God sex er healende og en af forudsætningerne for et velfungerende
forhold, mener Irina Andersen, der ved hjælp af vaginal akupressur kan
afhjælpe problemer med underlivet og sexlivet.
Eksempel på en forkert
bøjet tommelfinger:
Mange kvinder har problemer med underlivet og sexlivet. De døjer med
krampe og svie og har måske svært ved at få orgasme. Irina Andersen
er kvinden, der tager over, hvor mange læger giver op. Hun kan som den
eneste i Danmark behandle med den gamle tantriske behandlingsform
vaginal akupressur.
Vaginal accupressur
Ligesom zoneterapi forløser vaginal akupressur fysiske og psykiske
problemer ved hjælp af tryk med fingrene. Men hvor zoneterapiens
tager udgangspunkt i fødderne, arbejder den vaginale akupressur med
tryk indeni og udenpå skeden, på hofterne lænden og ryggen.
– Hvor huden under fødderne er meget grov, er vaginaen noget af det
fineste, hvilket betyder, at denne behandling er meget effektiv,
fortæller Irina.
Eksempel på en rigtig
bøjet tommelfinger:
Vaginal akupressur kan afhjælpe:
- Krampe, svie og kløe i skeden
- Ubehag ved elskov
- Skedekrampe
- Problemer med at få orgasme
- Problemer i forbindelse med fødsel og graviditet
- Tilbagevendende svamp og blærebetændelse
- Incest- og overgrebsproblematikker
Stort erotisk potentiale
Selvom det er en meget intim behandlingsform, oplever kvinderne, der
kommer hos Irina, det sjældent som noget ubehageligt.
Vi er da meget mere objektive I vores
aktuelle moderne behandling ?
Diabetes today (Type II, NIDDM)
Treatment:
Dietary counseling and a strict diet, insulin sensitizers/secretion stimulants
Diabetes units are manned with doctors and dieticians
There are no physiotherapist and no training centres
Diabetes is a muscle disease !
Diabetes and impaired glucose tolerance: main reason is lack of exercise
Exercise in the untrained can double or triple insulin sensitivity
Hvorledes rankeres (videnskabelig) evidence ?
Adams H, Brott T, Furland A, Gomez C, Grotta J, Helgason C et al.
Guidelines for the managment of patients with acute ischemic stroke. Astatement
for healthcare professionals from a special writing group of the stroke counsil,
American Heart Association
Stroke 1994; 25:1901-14
Kaste M, Olsen TS, Orgogozo J-M, Bogousslavsky J, Hacke W for the EUSI
Excecutive Committee
Organization of stroke care, Education, Stroke Units and Rehabilitation
Cerebrosvasc Dis 2000;10(suppl 3): 1-11
The hierarchy of clinical evidence:
Level I: Highest level of evidence
primary endpoints from randomized, double-blinded study with
adequate sample size
properly performed meta-analysis of quality outstanding randomized
trials
Level II: Intermediate level of evidence
randomized, non-blinded trials
small randomized trials
pre-defined secondary end-points of large randomized trials
Level III: Lower level of evidence
prospective case series with concurrent or historical control
epidemiology
post hoc analyses of randomized trials
governmental or other public clearing reports
Level IV: undetermined level of evidence
case reports
small case series without control
general agreement despite lack of scientific evidence from controlled
trials
TABLE 1. GRADES OF EVIDENCE FOR THE PURPORTED
QUALITYOF STUDY DESIGN *
I
Evidence obtained from at least one properly randomized,
controlled trial.
II-1 Evidence obtained from well-designed controlled trials
without randomization.
II-2 Evidence obtained from well-designed cohort or case–control
analyticstudies, preferably from more than one center or
research group.
II-3 Evidence obtained from multiple time series with or without
the intervention. Dramatic results in uncontrolled
experiments (such as the results of the introduction of
penicillin treatment in the 1940s) could also be regarded as
this type of evidence.
III Opinions of respected authorities, based on clinical
experience; descriptivestudies and case reports; or reports
of expert committees.
*The grades are those of the U.S. Preventive Services Task Force.
2nd ed. Baltimore: Williams & Wilkins, 1996
Concato J, NEJM 2000;342:1887-92
Why Control ? Why Randomization
One statistician to another:
How’s your wife?
Compared to what !
Disease
activity
Nosocomial
border
spring autumn
Time
Randomized controlled clinical trials:
What happens if we treat patients ?
(take patients, treat and see if they are better than non-treated)
ex. Treat patients with lipid lowering drugs or placebo
ex. Beta-carotene induces lung cancer in drinking smokers
Epidemiology (cohort studies):
Which characteristics do survivors show ?
establish a cohort, ask how much they exercise, monitor survival
ex. American Physician Health study
½ hour exercise daily gives lower CVD
ex. High intake of beta-caroten in diet is associated with low CVD
ex. Low body weight in high age is associated with poor survival
is it dangerous to diet at high age ?
BMJ 1996;312:71-72 (13 January)
Editorials
Evidence based medicine: what it is and what it isn't
“It's about integrating individual clinical expertise and the best
external evidence”
“Evidence based medicine, whose philosophical origins extend back to
mid-19th century Paris and earlier, remains a hot topic for clinicians,
public health practitioners, purchasers, planners, and the public.”
“the Cochrane Collaboration and Britain's Centre for Review and
Dissemination in York are providing systematic reviews of the
effects of health care; new evidence based practice journals are
being launched; and it has become a common topic in the lay media”
“Evidence based medicine is the conscientious, explicit, and judicious
use of current best evidence in making decisions about the care of
individual patients”
“Evidence based medicine is neither old hat nor impossible to
practice”
”Errors” in clinical trials:
The classical errors:
Type I and Type II errors
difference due to chance, overse a true difference
Other errors
Type III erors:
Wrong statistical method
Wrong patient group
Wrong diagnosis
Wrong primary variable
Wrong design
……
Wrong strategy (commercially inspired)
Wrong comparison (placebo ? best available treatment?
……
no ”intention to treat analysis”
Type IV errors:
Doing the study for the ”wrong reasons”
Publication bias:
Bekelman JE JAMA. 2003;289:454-465.
Data Synthesis Aggregating the results of these
articles showed a statistically significant association
between industry sponsorship and pro-industry
conclusions (pooled Mantel-Haenszel odds ratio, 3.60;
95% confidence interval, 2.63-4.91). Industry
sponsorship was also associated with restrictions on
publication and data sharing. The approach to
managing financial conflicts varied substantially
across academic institutions and peer-reviewed
journals.
Conclusions Financial relationships among industry,
scientific investigators, and academic institutions are
widespread. Conflicts of interest arising from these
ties can influence biomedical research in important
ways.
Comparing risks
Relative risk
Odds ratio
prospective study
retrospective study
RR=
a/(a+c)
b/(b+d)
OR = ad/bc
Prospective classification
Retrospective classification
Yes
No
Gr 1
a
c
a+c
Gr 1
b
d
b+d
a+b
c+d
To what degree is evidence based medicine practiced in Denmark ?
No certains estimates:
Qualified guess:
Hierachy of specialities:
(prob heavy biassed)
maybe about 10-25 %
Cardiology (medical)
Oncology (medical)
Psychiatry
anestesiology emergency medicine
toxicology
surgery
Why power calculation (1 of 3) ?
Simplified estimate of number of observations
N1 = N2 = 2(t2α,df + tβ,df )2 x (CV2 / MERIDIF2)
•
•
•
•
t-values can be obtained from a statistical t-table,
SD is the standard variation of the measurement
MERIDIF is the Minimum RElevant DIfference.
If N1 = N2 is large t-values are about 2 and 1.7.
N1 = N2 = 2(2+1.7)2 x ( SD2 / MERIDIF2) = 27.4 x (SD2 / MERIDIF2)
30 x (CV2 / MERIDIF2) or
30 (CV /MERIDIF)2
[1] http://www.ebook.stat.ucla.edu/calculators/powercalc/
[2] http://www.davidmlane.com/hyperstat/power.html/
Statistica 6.0
N1=n2= 30x (0,2/0,2)2 = 30
(stat: 23)
N1=n2= 30x (0,2/0,1)2 = 120
(stat: 86)
Independent Sample t-Test: Sample Size Calculation
Two Means, t-Test, Ind. Samples (H0: Mu1 = Mu2)
N vs. Power (Alpha = 0,05, Es = -0,5)
110
Required Sample Size (N)
100
90
80
70
60
50
40
0,6
0,7
0,8
Power Goal
0,9
1,0
Why Number needed to treat (NNT)?
NNT =
1
p1 – p2
NNT = number needed to treat to avoid one case
p1 = observed incidence without treatment
p2 = observed incidence with treatment
Ex. Pneumococ vaccination
p1= 20/100.000, 70% treatment effect, mortality 20%
NNT = 7143 (sepsis); NT = 35.714 (death)
Relation between sample size (SS) and NNT
SS
calculation for obtaining significant results
NNT treatment ”efficacy” in public health terms,
dependent on incidence and efficacy.
If SS is very great one should consider if the trial
should be done, and whether it is an efficient
treatment
NEJM 2000; 342:1887-92
Epidemiology versus controlled intervention studies
z RCT
 observational
Concato NEJM 342;25:1887-92
Antioxidant trials
Epidemiology consistantly indicate cancer and CVD protection
RCT gives conflicting indication
no effect
positive effect
negative effect
The ALLHAT study
Controlled trial
(JAMA 288:2981-2997 and 2998-3007)
diuretic chlorthalidone (Hygroton Novartis)
Ca-blokker
amlodipine (Norvasc, Pfizer)
ACE-hæmmer lisinopril (Vivatec MSD, Zestril Zenica)
chlorthalidone
amlodipine
lisinopril
12,5 – 25 mg
2.5 – 10 mg
10 -40 mg
(0.25 – 0.50 kr [1999])
(0.75 – 3,00 kr)
(1.15 – 4,60 kr)
Initieret af NIH
Pris
US$ 125 mio
Rekruitment
Feb 1994 – March 31 2002
N
33.357 med hypertension + 1 CHD risiko faktor
Outcome
1: fatal CHD, non-fatal AMI, intention to treat.
2: all-cause mortality, stroke, +++
Dec 9, 2002
Recent test results are startling. In the largest hypertension clinical trial ever
conducted, an eight-year study involving more than 42,000 patients, a diuretic
actually proved more effective than the newer drugs in lowering blood
pressure and preventing cardiovascular complications.
BMJ 2004, 326:170 Spind doctors soft pedal on antihypertensives:
ALLHAT study JAMA 2002;288:2981-97
Ugeskrift for Læger · 14. april 2003, nr. 16
Har det offentlige en selvstændig forskningsmæssig rolle i lægemiddeludviklingen?
STATUSARTIKEL
Henrik Enghusen Poulsen & Thor Buch Grønlykke