AREA CRITICAL APPRAISAL
INTRODUZIONE ALLA VALIDITA‟ ESTERNA
© dott. Alessandro Battaggia
Popolazione
Generale
RCT
?
Singolo
Paziente
?
PROVE DI
EFFICACIA
da Noventa 2004 modificata
Pazienti reclutati nei RCT
Pazienti reali
Da Macchia, 2004, modificata
Validità
interna
Randomised
Controlled
Trial
Quasisperimentale
Osservazionale
Trasferibilità
Elementi della trasferibilità
1.
Partecipanti: sono simili alla gente reale? Sono stati reclutati
nello stesso setting?
2.
Malattia: è la stessa del mio paziente?
3.
Interventi : è lo stesso setting? cosa assume il braccio di
intervento? e il braccio di controllo? La dose è realistica? ll
follow-up è realistico?
4.
Outcome: E' importante per la salute? Come sono stati
interpretati i risultati? Le conclusioni del trial vengono
comunicate in modo corretto? Ci possono aiutare i
sottogruppi?
5.
Rischio/efficacia: vale la pena adottare l’ intervento?
1- PARTECIPANTI
..somigliano ai miei pazienti?
I.
Confrontabilità dei due bracci all' inizio e
durante lo studio
II.
Eventi precedenti la randomizzazione
(arruolamento, refusers, run in)
III.
Eventi successivi alla randomizzazione
(perdite, non Compliance )
I.
Confrontabilità tra i due bracci
A.
Caratteristiche basali: tabella 1
STUDIO HOPE
Nejm 2000 342:145
B.
Rischio basale : rischio dei controlli
STUDIO HOPE
Nejm 2000 342:145
Pazienti con eventi CHD (%)
30
25,2%
Prevenzione
secondaria
NNT = 18
25
HPS-placebo
20
15
19,8%
NNT = 91
HPS-Statina
Prevenzione
primaria
10
5
3%
1,9%
ASCOT-placebo
0
90
ASCOT-Statina
110
130
150
170
190
Valori medi di C-LDL al follow-up (mg/dl)
Heart Protection Study Collaborative Group, Lancet 2002; 360:7-22 - Sever PS et al., for the ASCOT Investigators, Lancet 2003; 361:1149-58
210
B.
Confrontabilità nel corso della ricerca: curve
di sopravvivenza
Ridker PM et al.
Nejm 2005 352
Notate qualcosa?
Manson JE et al
Nejm 2003 349:6
Notate qualcosa?
Bresalier R et al.
Nejm 2005 352:1092
II.
Eventi precedenti la randomizzazione
Popolazione generale
BASE STUDY
CONTATTATI
Non rispondono ai criteri di inclusione
Qualified
ELEGGIBILI
Rifiutano
Esclusi in fasi di RUN-IN
Rando
mised
ELETTI
Final report on the aspirin component of the
ongoing Physicians' Health Study.
Steering Committee of the Physicians' Health Study Research Group
The Physicians' Health Study is a randomized,
double-blind, placebo-controlled trial designed to
determine whether low-dose aspirin (325 mg every
other day) decreases cardiovascular mortality and
whether beta carotene reduces the incidence of
cancer. The aspirin component was terminated
earlier than scheduled, and the preliminary findings
were published. We now present detailed analyses of
the cardiovascular component for 22,071
participants, at an average follow-up time of 60.2
months. There was a 44 percent reduction in the risk
of myocardial infarction (relative risk, 0.56; 95 percent
confidence interval, 0.45 to 0.70; P less than
0.00001) in the aspirin group (254.8 per 100,000 per
year as compared with 439.7 in the
A slightly increased risk of stroke among those
taking aspirin was not statistically significant; this
trend was observed primarily in the subgroup with
hemorrhagic stroke (relative risk, 2.14; 95 percent
confidence interval, 0.96 to 4.77; P = 0.06). No
reduction in mortality from all cardiovascular causes
was associated with aspirin (relative risk, 0.96; 95
percent confidence interval, 0.60 to 1.54). Further
analyses showed that the reduction
“no reduction in mortality was found (RR 0.96 CI0.60-1.54) ..aspirin
for the primary prevention of cardiovascular disease demonstrates
a conclusive reduction in the risk of myocardial infarction (RR 0.56
CI 0.45-0.70)”
NEJM 1989 321:129-135
Physicians' Health Study
Base-Study
261.248 iscritti AMA
contattati
112.528
59.285
adesioni
52%
148.720
NON HANNO RISPOSTO
53.243
NON HANNO ACCETTATO
33.223
eleggibili
22.071
56%
eletti
66%
26.062
NON ELEGGIBILI
11.152
ESCLUSI IN RUN-IN
Randomizzati: 8% dei contattati
43%
risposte
Il campione Physicians' Health Study
•
•
•
•
•
•
•
•
•
•
Erano i più motivati (hanno risposto e aderito)
Erano medici (conoscevano i fattori di rischio cardiovascolare)
Erano maschi
Erano relativamente giovani (53a)
Pochi diabetici (2.4%)
Pochi ipertesi (PAS >150 4%; PAD >90 9%)
Pochi obesi (25% sovrappeso)
Pochi fumatori (11%)
Molti sportivi (71%)
Tasso Basale di Infarto = 4 per mille /anno
Randomised trial of cholesterol lowering
in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study
(4S)
[No authors listed]
Drug therapy for hypercholesterolaemia has
remained controversial mainly because of
insufficient clinical trial evidence for improved
survival. The present trial was designed to
evaluate the effect of cholesterol lowering with
simvastatin on mortality and morbidity in
patients with coronary heart disease (CHD).
4444 patients with angina pectoris or previous
myocardial infarction and serum cholesterol
5.5-8.0 mmol/L on a lipid-lowering diet were
randomised to double-blind treatment with
simvastatin or placebo.
Over the 5.4 years median follow-up period,
simvastatin produced mean changes in total
cholesterol, low-density-lipoprotein cholesterol, and
high-density-lipoprotein cholesterol of -25%, -35%,
and +8%, respectively, with few adverse effects. 256
patients (12%) in the placebo group died, compared
with 182 (8%) in the simvastatin group. The relative
risk of death in the simvastatin group was 0.70 (95%
CI 0.58-0.85, p = 0.0003). The 6-year probabilities of
survival in the placebo and simvastatin groups were
87.6% and 91.3%, respectively. There were 189
coronary deaths in the placebo group and 111 in the
simvastatin group (relative risk 0.58, 95% CI 0.460.73)
“There were 256 deaths in the placebo group and 182 in the
simvastatin group (relative risk of death 0.70 95% CI 0.58-0.85) ..
this study shows that long-term treatment with simvastatin
improves survival in CHD patients”
Lancet 1994 Nov 19;344(8934):1383-9
Scandinavian Simvastatin Survival Study
7027
potenzialmente
4444
eleggibilli
eletti
63,2%
N..?
NON ELEGGIBILI
2164 CON LIPIDEMIA NON IDONEA
396 HANNO RIFIUTATO
23
..?
Randomizzati: 63% eleggibili
Base Study: n..? pazienti
afferenti a 94 cliniche
Campione Scandinavian Simvastatin Survival Study
•
•
•
•
•
•
•
•
•
Parecchi i criteri di esclusione
Soggetti scandinavi (rischio cardiovascolare maggiore nei nordici)
Prevalentemente maschi (intorno 80%)
Età massima 70 anni
Prevalentemente infartuati (intorno 80%)
Clinicamente stabili (sono state escluse le angine instabili)
Solo CHD (assenti altre patologie CVD)
Parecchi Fattori di Rischio cardiovascolare
Mortalità basale (incidenza cumulativa) = 0, 123 in sei anni
HOPE
10.576
eleggibili
90,2%
90,2%
9541
eletti
N..?
NON ELEGGIBILI
1035
ESCLUSI IN UNA FASE DI RUN-IN
Randomizzati: 90.2% eleggibili
Base-Study:
n..? pazienti a rischio CVD
Campione HOPE
•
•
•
•
Anziani
Maschi circa 70%
VasculopaticI (Metà circa infartuatI, Quasi metà con vasculopatia periferica)
Molti fattori di RischiO (Familiarità per CHD circa 80%; BMI medio 28;
Diabetici circa 40%; Ipertesi quasi metà
• Rischio Basale per End-point primario (morte, IM, Stroke) = 0.17
III.
Eventi successivi alla randomizzazione
Eventi successivi alla
randomizzazione
R
Intervento
Controllo
Persi al follow-up
Non compliant
(drop-ins o
cross-overs)
Non compliant
(drop-outers)
Compliant
Standard CONSORT 1996
70
Compliance agli antiipertensivi (studio osservazionale)
60
60
53
50
47
40
30
20
20
14
11
10
0
6 mesi
DIURETICI
4,5 anni
CALCIOANTAGONISTI
JAMC 1999 160:1
ACEINIBITORI
I pazienti dei trials sono più motivati !
Physicians' Health Study
• persi al follow-up : nd
• non compliant : 10%
22.071 medici randomizzati
NEJM 1989 321:129-135
HOPE
• persi al follow-up: 0.01% (n=6!)
• non compliant : 30%
9.541 pazienti ad alto rischio CVD randomizzati
NEJM 2000 342:145-153
Scandinavian Simvastatin
Survival Study (4-S)
4.444 Pazienti coronaropatici randomizzati
Lancet 1994 Nov 19;344(8934):1383-9
• persi al follow-up: zero!
•10% non compliant
2- DISEASE
..è la stessa malattia dei miei pazienti?
Scompenso cardiaco: incidenza per sesso ed età:
The Framingham Heart Study
TRIAL
90
80
70
60
50
40
30
20
Mean Age
Val-HeFT (I)
Val-Heft (II)
Consensus
Solvd
Elite (I)
Elite (II)
Peoved
Radiance
Dig
MDC
Cibis
US carvedilol T.
A-NZ carvedilol T.
Merit-HF
Atlas
Cibis
Rales
Diamond-CHF
WHOSE
POPULATION ?
58
61
71
61
73
71
64
60
63
49
59
58
67
64
64
61
61
70
RCT POPULATION
10
0
45-54
55-64
65-74
75-84
85-94
I GAP tra l’ ideale (RCT) e il reale : lo scompenso
RCT
Popolazione reale
Età media (anni)
60
75
Prevalenza femmine
20%
50-60%
Comorbidità (BPCO – Demenza – Parkinson –
Anemia – Depressione- Insuff. Epatica - cancro)
 0-5%
30-40%
Prevalenza del diabete
15-20%
40%
Prevalenza IRC
0%
10 – 20%
Terapie concomitanti
scarse
di solito molte
Pazienti con FE misurata
 90-100%
30-40%
Pazienti con FE normale
 0-10
50%
Compliance (Run-in period)
90-100%
NA
Effetti collaterali
Bassi
??
Compliance alla terapia
Alta
Bassa
SOLVD 1990
Enalapril
riduce mortalità e ricoveri per HF nei pazienti con FE <0.35
RRR = 0.26
MERIT-HF 2000
Metoprololo
riduce la mortalità e i ricoveri per Scompenso Cardiaco nei
pazienti II-IV NYHA con FE <0.40
RRR = 0.31
RALES 2000
Spironolattone
riduce la mortalità nei pazienti III o IV NHYA trattati con
ACEi e Diureticie con FE <0.35
RRR = 0.30
Criteri di arruolamento dei tre trials salvavita
SOLVD
MERIT HF
RALES
Arruolamento: FE < 35 %
Arruolamento : FE < 40%
+ NYHA II-IV
Arruolamento: FE < 35%
+ NYHA III-IV
Drug related exclusion criteria
Drug related exclusion criteria
Drug related exclusion criteria
Aortic Stenosis
COPD
Aortic Stenosis
Unstable angina
Unstable angina
Valvular disease
Recent AMI
Recent AMI
Congenital heart disease
Creatinine > 2.0 mg %
Heart transplant
Heart transplant
Known intolerance to ACE-I
Unstable angina
Age > 80 years
K > 2.5 mg%; Cr > 2.5 mg %
Other exclusion criteria
Other exclusion criteria
Other exclusion criteria
Dementia, liver failure, cancer
Age > 80 years
Dementia, liver failure, cancer
Dementia, liver failure, cancer
% obbedienza ai criteri di inclusione dei tre trials di 20.388 pazienti di età > 64 anni
SOLVD
per circa l‟ 80%
dei pazienti
anziani
scompensati
mancano
evidenze
sulla terapia!
18 %
MERIT
HF
13 %
RALES
Masoudi FA et al Am Heart J. 2003 146:250
25 %
3- INTERVENTI
10 mg die
..somigliano a quelli sui miei pazienti?
Gastrointestinal Toxicity With Celecoxib
vs Nonsteroidal Anti-inflammatory Drugs
for Osteoarthritis and Rheumatoid
Arthritis
The CLASS Study: A Randomized
Controlled Trial
Fred E. Silverstein et al
Context Conventional nonsteroidal anti-inflammatory
drugs (NSAIDs) are associated with a spectrum of toxic
effects, notably gastrointestinal (GI) effects, because of
inhibition of cyclooxygenase (COX)-1. Whether COX-2–
specific inhibitors are associated with fewer clinical GI
toxic effects is unknown
Results For all patients, the annualized incidence rates of
upper GI ulcer complications alone and combined with
symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs
1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively.
For patients not taking aspirin, the annualized incidence rates
of upper GI ulcer complications alone and combined with
symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs
1.27% (P = .04) and 1.40% vs 2.91% (P = .02).
„celecoxib was associated with a lower incidence
of symptomatic ulcers and ulcer complications
combined‟
JAMA. 2000;284:1247-1255
CLASS Study
7.968 pazienti
N=3987
400 mg x 2
N=1985
800 mg x 3
N=1996
75 mg x 2
3bis - Comparator?
.. è importante anche il trattamento
di controllo!
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
Intervento
Pazienti
arruolati
Allocation
Controlli
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
ARc
Intervento
1) Arruolare pazienti
ad alto rischio
Allocation
Controlli
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
ARR
2)
Aumentare
l'Intervento
intervento
ARc
1) Arruolare pazienti
ad alto rischio
Allocation
Controlli
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
ARR
2)
Aumentare
l'Intervento
intervento
ARc
1) Arruolare pazienti
ad alto rischio
Allocation
3) Fiaccare
il controllo
(->placebo)
ARR
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
ARR
2)
Aumentare
l'Intervento
intervento
ARc
1) Arruolare pazienti
ad alto rischio
Allocation
3) Fiaccare
il controllo
(->placebo)
ARR
Aumentare il sample size
..seguono alcuni esempi che potrebbero essere stati estratti dalla
peggior letteratura..
[1911-1979?]
Josef Mengele, the infamous doctor
of Auschwitz, commonly referred to
as the "Angel of Death".
The delayed-emesis syndrome from cisplatin:
phase III evaluation of ondansetron
versus placebo.
Gandara DR et al.
Cisplatin may evoke both an acute emetic response during the
first 24 hours following treatment and a less well-recognized
syndrome of delayed emesis. While delayed emesis is usually
less severe in terms of frequency of vomiting episodes, the
problem continues to result in significant morbidity. In
comparison with acute emesis, the exact pathogenesis of the
delayed emesis syndrome remains unclear
A phase III multicenter study has evaluated oral
ondansetron versus placebo in the prevention of the
delayed-emesis syndrome in 50 patients during days
2 through 5 following high-dose cisplatin
administration. Although the daily rates of complete
emetic control, failure, and
“Ondansetron was well tolerated in the dose
and schedule used.”
Semin Oncol. 1992 Aug;19(4 Suppl 10):67-71.
"Anche a piccole dosi la proclorperazina è un trattamento
antiemetico efficace"
Citron ML.Ann Intern Med. 1993 Mar 15;118(6):470-1.
Low-dose cyclosporin versus placebo in
patients with rheumatoid arthritis
Tugwell P, et al
144 patients with severe rheumatoid arthritis
from six centres were randomised to receive
oral cyclosporin or placebo for 6 months. The
initial daily dose of cyclosporin was 2.5 mg/kg,
which was increased cautiously with
monitoring of serum cyclosporin levels and
creatinine; the mean stabilisation dose was 3.8
mg/kg.
There were significant improvements in the
cyclosporin-treated patients compared with
the controls in the major outcomes of
reduction of active joints (23% improvement),
pain (24%), and functional status (16%);
global improvement was 27%. In the
cyclosporin group serum creatinine increased
by a mean of 15.6 mumols/l and mean arterial
blood pressure by 6.27 mmHg; these
increases were controlled in all but 2 patients
by dose adjustment without withdrawal from
the study.
“There were significant improvements in the
cyclosporin-treated patients compared with the
controls in the major outcome”
Lancet. 1990 May 5;335(8697):1051-5.
" nel 1960 il Plaquenil è stato introdotto come efficace
opzione terapeutica nella Artrite reumatoide"
http://remedyfind.com/rm-783-Plaquenil.asp
A placebo-controlled trial of paroxetine in the
treatment of major depression.
Smith WT, Glaudin V
Paroxetine is a phenylpiperidine compound that
selectively inhibits neuronal serotonin uptake in
man. In this study, the efficacy of paroxetine was
compared with that of placebo in the treatment of
66 outpatients with the diagnosis of moderate-tosevere major depression. The research was a 6week, prospective, double-blind design after a 1week placebo baseline phase.
Paroxetine was associated with a consistent
pattern of greater improvement on the primary
efficacy scales, but the differences were not
statistically significant. Paroxetine did produce
significantly greater improvement than placebo
for patients whose illness had lasted more than 1
year, and there was a significant reduction in
suicidal ideation.
“Paroxetine did produce significantly greater
improvement than placebo for patients whose
illness had lasted more than 1 year, and there
was a significant reduction in suicidal ideation”
Clin Psychiatry 1992 Feb;53 Suppl:36-9
Sono a disposizione ormai da 30 anni efficaci
Rimedi farmacolotgici contro la depressione(1992)
Rickels K et al J Clin Psychiatry 1992; 53:Suppl:27-29
Double-blind, placebo-controlled study of the
efficacy of flosequinan in patients with chronic
heart failure. Principal Investigators of the
REFLECT Study.
OBJECTIVES. The aim of this study was to assess the efficacy of
flosequinan in chronic heart failure. BACKGROUND. Flosequinan
M. et al drug that acts by interfering with the inositolisPacker
a new vasodilator
triphosphate/protein kinase C pathway, an important mechanism
of vasoconstriction. The drug dilates both peripheral arteries and
veins, is
RESULTS. After 12 weeks, maximal treadmill exercise
time increased by 96 s in the flosequinan group but by
only 47 s in the placebo group (p = 0.022 for the
difference between groups). Maximal oxygen
consumption increased by 1.7 ml/kg per min in the
flosequinan group (n = 17) but by only 0.6 ml/kg per
min in the placebo group (n = 23), p = 0.05 between
the groups. Symptomatically, 55% of patients receiving
flosequinan but only 36% of patients receiving placebo
benefited from treatment (p = 0.018
“These findings indicate that flosequinan is an
effective drug for patients with chronic heart
failure who remain symptomatic despite
treatment with digoxin and diuretic drugs”
J Am Coll Cardiol. 1993 Jul;22(1):65-72
Gli ACE inibitori rappresentano una terapia
di riferimento per lo scompenso cardiaco (1991)
Braunwald E NEJM 1991 325:351
Nb: esistono anche i placebo mascherati
da farmaco di confronto 
4- FOLLOW-UP
..è realistico?
PROTOCOLLO STUDIO G.A.I.A. 2003
Studio Prima-Poi
Partecipanti : MMG
Intervento: Programma educazionale
Outcome:
•Incidenza di eventi cardio-cerebro-vascolari
•Modifica prima-poi dello score MMES
•Modifica prima-poi dello score del rischio CV globale
Follow-up: due anni
5- INTERPRETAZIONE
DEI RISULTATI
..è corretta?
troppo spesso si insiste solo
sullla „significatività statistica‟
A prospective trial of intravenous streptokinase
in acute myocardial infarction (I.S.A.M.).
Mortality, morbidity, and infarct size at 21 days.
The I.S.A.M. Study Group
Within six hours after the onset of symptoms of
myocardial infarction, we randomly assigned 1741
patients up to 75 years of age to a one-hour intravenous
infusion of 1.5 million IU of streptokinase or placebo. At
21 days mortality was 6.3 percent in the streptokinase
group and 7.1 percent in the placebo group. Of those
treated within three hours of the onset of symptoms, 5.2
percent died in the streptokinase group (n = 477), as
compared with 6.5 percent in the placebo group (n = 463).
These differences were not significant.
Angiograms obtained in 848 patients three to four weeks
after infarction revealed that the streptokinase group had
higher global ejection fractions (56.8 vs. 53.9 percent, P
less than 0.005) and regional ejection fractions (all patients
in group, P less than 0.005; patients with anterior or inferior
infarctions, P less than 0.05). We conclude that beginning
intravenous streptokinase infusion early after the onset of
myocardial infarction limits the size of the infarct regardless
of its localization.
“three to four weeks after infarction the streptokinase group had higher global ejection
fractions (56.8 vs. 53.9 percent, P less than
0.005)”
NEJM 1986 314:1465
.. a che cosa ci serve questo risultato 'significativo??
un‟ idea più realistica può essere fornita dal
Number Needed to Treat
(NNT)
Se si parla di un evento indesiderato si chiama
Number Needed to Harm
(NNH)
Il problema dei punti di vista..
NNT= n° pazienti da trattare per avere un outcome
(NNT-1)= n° pazienti da trattare inutilmente
per avere un outcome
Randomised trial of cholesterol lowering
in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study
(4S)
[No authors listed]
Drug therapy for hypercholesterolaemia has
remained controversial mainly because of
insufficient clinical trial evidence for improved
survival. The present trial was designed to
evaluate the effect of cholesterol lowering with
simvastatin on mortality and morbidity in
patients with coronary heart disease (CHD).
4444 patients with angina pectoris or previous
myocardial infarction and serum cholesterol
5.5-8.0 mmol/L on a lipid-lowering diet were
randomised to double-blind treatment with
simvastatin or placebo.
Over the 5.4 years median follow-up period,
simvastatin produced mean changes in total
cholesterol, low-density-lipoprotein cholesterol, and
high-density-lipoprotein cholesterol of -25%, -35%,
and +8%, respectively, with few adverse effects. 256
patients (12%) in the placebo group died, compared
with 182 (8%) in the simvastatin group. The relative
risk of death in the simvastatin group was 0.70 (95%
CI 0.58-0.85, p = 0.0003). The 6-year probabilities of
survival in the placebo and simvastatin groups were
87.6% and 91.3%, respectively. There were 189
coronary deaths in the placebo group and 111 in the
simvastatin group (relative risk 0.58, 95% CI 0.460.73)
“There were 256 deaths in the placebo group and 182 in the
simvastatin group (relative risk of death 0.70 95% CI 0.58-0.85) ..
this study shows that long-term treatment with simvastatin
improves survival in CHD patients”
Lancet 1994 Nov 19;344(8934):1383-9
HOPE
HOPE
ci aiutano anche gli intervalli di confidenza
della stima del valore di efficacia (es: del NNT)
Intervalli di confidenza e dimensione dell' effetto
Meglio con
il trattamento
Peggio con
il trattamento
grande
grande
piccola
piccola
CUT OFF
Intervalli di confidenza e precisione della stima
Meglio con
il trattamento
Peggio con
il trattamento
precisa
imprecisa
precisa
Imprecisa
CUT OFF
Double-blind randomized trial of tramadol
for the treatment of the pain of diabetic
neuropathy.
Harati Y et al
OBJECTIVE: The objective of this study
was to evaluate the efficacy and safety
of tramadol in treating the pain of
diabetic neuropathy. BACKGROUND:
The pain of diabetic neuropathy is a
major cause of morbidity among these
patients and treatment, as with other
small-fiber neuropathies, is often
unsatisfactory. Tramadol is a centrally
acting analgesic for use in treating
moderate to moderately severe pain.
METHODS:
RESULTS: Tramadol, at an average dosage
of 210 mg/day, was significantly (p < 0.001)
more effective than placebo for treating the
pain of diabetic neuropathy. Patients in the
tramadol group scored significantly better in
physical (p=0.02) and social functioning
(p=0.04) ratings than patients in the placebo
group. No statistically significant treatment
effects on sleep were identified. The most
frequently occurring adverse events with
tramadol were nausea, constipation,
headache, and somnolence
“The results of this placebo-controlled trial
showed that tramadol was effective and safe in
treating the pain of diabetic neuropathy.”
Neurology. 1998 Jun;50(6):1842-6.
Outcome (1) = pain relief
ARp = 23/64
ARt = 43/63
Outcome (2) = Side effects
ARp = 1/64
ARt = 9/63
Outcome (1) = pain relief
ARp = 23/64
ARt = 43/63
Outcome (2) = Side effects
ARp = 1/64
ARt = 9/63
Poco conosciuta è la LHH
Likelihood to be Help vs to be Harm
=(1/NNT)/(1/NNH)
Likelihood to be Help vs to be Harm
LLH = (1/NNT)(1/NNH) = (1/3)(1/8) =2.6
Quattro metodi per ‘gonfiare’ l’ efficacia dell'
intervento
ARR
2)
Aumentare
l'Intervento
intervento
ARc
1) Arruolare pazienti
ad alto rischio
Allocation
3) Fiaccare
il controllo
(->placebo)
ARR