From Clinical Trial Evidence to
Practice Guidelines
Lost in Translation
Sanjay Kaul, MD, FACC
George A. Diamond MD, FACC
Division of Cardiology
Cedars-Sinai Medical Center and
Geffen School of Medicine at UCLA
Los Angeles, California
Complexity of American Strategy in Afghanistan
“When we understand that slide, we’ll have won the war” - General McChrystal
Complexity of Evidence-Based Medicine
Lost in a jungle of evidence, we need a compass
Evidence to Guidelines
Lost in Translation
Key Issues for Discussion
•
Establish the scientific evidence
- Appraise and synthesize the evidence
•
Elucidate the clinical context
- Clinical importance vs. statistical significance
- Clinically relevant weighted outcomes
•
Encourage optimal processes of care
- Quality initiatives
- Reimbursement initiatives
Appraisal of Evidence
Design and Methods
 Quality
• Important limitations
- Study design or execution (bias)
- Lack of randomization
- Lack of concealment
- ITT principle violated
- Inadequate blinding
- Loss to follow-up
- Early stopping for benefit
- Inconsistency of results
- Indirectness of results
- Imprecision
- Publication bias
 Quality
• Special strengths
- Randomized, controlled, prospective,
double-blind trials
- Large, consistent, and precise
treatment effect
- RR<0.5 or >2.0 (large)
- RR<0.2 or >5.0 (very large)
- Minimal confounding & bias
Synthesis of Evidence
ACC/AHA Clinical Practice Guidelines
Class I
(“Useful &
Effective”)
(Benefit >>> risk)
(Highly
recommended)
Level A
(Multiple randomized
clinical trials)
Level B
(Single randomized
trial or
nonrandomized
studies
Level C
(Consensus opinion,
case studies, or
standard of care)
Class II
(“Conflicting Evidence”)
IIa
(Benefit >>risk)
(Reasonably
recommended)
IIb
(Benefit ? risk)
(May be
considered)
Class III
(“Not useful/
effective, may be
harmful”)
(No benefit/Harm)
(Not recommended)
Evidence to Guidelines
Lost in Translation
Self-evident Truths
•
Does empirical evidence trump expert opinion?
Scientific Evidence Underlying The ACC/AHA
Clinical Practice Guidelines
Level of Evidence A
AF
11.7
Heart failure
26.4
PAD
15.3
STEMI
13.5
Perioperative
12
Secondary prevention
22.9
Stable angina
6.4
SV arrhythmia
6.1
UA/NSTEMI
23.6
Valvular disease
0.3 (1/320)
VA/SCD
9.7
PCI
11
CABG
19
Pacemaker
4.9
Radionuclide imaging
4.9
0
10
20
Tricoci P et al. JAMA 2009
30
Scientific Evidence Underlying The ACC/AHA
Clinical Practice Guidelines
Level of Evidence C
AF
58.6
Heart failure
54.3
PAD
25.1
STEMI
47.2
Perioperative
32
Secondary prevention
8.3
Stable angina
54.5
SV arrhythmia
56.5
UA/NSTEMI
29.6
Valvular disease
70.6
VA/SCD
58.5
PCI
47.8
CABG
20
Pacemaker
58.2
Radionuclide imaging
26.3
0
10
20
30
40
50
60
Tricoci P et al. JAMA 2009
70
80
ACC/AHA Clinical Practice Guidelines
Paucity of High-Quality Evidence
Class I
Class II
(Benefit >>> risk)
(Highly
recommended)
IIa
(Benefit >>risk)
(Reasonably
recommended)
IIb
(Benefit ? risk)
(May be
considered)
Class III
(Risk ? Benefit)
(Not
recommended)
Level A
19% based
Recommendations
are largely
developedare
from lower
on high-level
41% of guidelines
levels of evidence
opinion.
“Exercise
caution
evidence or expert
based
on Class
II
recommendations
when
not supported by
Level B considering recommendations
(Single
(”uncertain evidence”)
solid trial
evidence”
randomized
or
(Multiple
randomized
clinical trials)
nonrandomized
studies
Level C
(Consensus
opinion, case
studies, or
standard of care)
48% of guidelines are based on level C evidence
(“codification of expert opinion“)
Tricoci P et al. JAMA 2009
Scientific Evidence Underlying The
ACC/AHA Clinical Practice Guidelines
Caveat Emptor, Caveat Lector
“…it seems unlikely that substantial change will occur because
many guideline developers seem set in their ways. If all that can
be produced are biased, minimally applicable consensus
statements, perhaps guidelines should be avoided completely.
Unless there is evidence of appropriate changes in the guideline
process, clinicians and policy makers must reject calls for
adherence to guidelines. Physicians would be better off making
clinical decisions based on valid primary data”
Shaneyfelt and Centor, JAMA 2009
Guidelines that are driven by scientifically documented, high-quality
evidence are more likely to be accepted by the stakeholders, thereby
reducing the variability in care and improving the quality and cost of care
2009 ACC/AHA Focused Updates for STEMI/PCI
Paucity of High-Quality Evidence
Class I
(Benefit >>> risk)
(Highly
recommended)
Level A
(Multiple
randomized
clinical trials)
Level B
(Single
randomized trial or
nonrandomized
studies
Level C
(Consensus
opinion, case
studies, or
standard of care)
12% based
on high-level
evidence
Class II
IIa
(Benefit >>risk)
(Reasonably
recommended)
IIb
(Benefit ? risk)
(May be
considered)
Class III
(Risk ? Benefit)
(Not
recommended)
50% of guidelines are
based on Class II
recommendations
(“conflicting evidence”)
44% of guidelines are based on level C evidence
(“filtered expert opinion”)
Kushner FG, Hand M et al. 2009 Focused Updates, JACC/Circulation 2009
The Laws of Diminishing Objectivity
in the Interpretation of Evidence

vehemence 

-1
evidence
vehemence 
2
eminence
Peter McCulloch
The Lancet, 2004;363;9004
Evidence to Guidelines
Lost in Translation
Key Issues for Discussion
•
Establish the scientific evidence
- Appraise and synthesize the evidence
•
Elucidate the clinical context
- Clinical importance vs. statistical significance
- Clinically relevant weighted outcomes
•
Optimal processes of care
- Quality initiatives
- Reimbursement initiatives
ACC/AHA Clinical Practice Guidelines
Metrics for Assessing Strength of Evidence
• Effect size
- Absolute risk difference (NNT or NNH)
- Relative risk difference
Risk ratio
Odds ratio
Hazard ratio
•
Statistical certainty/precision
- Hypothesis testing (P value)
- Estimation (confidence interval)
•
? Clinical importance
Little or no explicit guidance
Disconnect Between Statistical
Significance and Clinical Importance
1
P value

Effect Size  Sample Size
Statistical significance  Clinical importance!
Statistical Significance vs. Clinical Importance
GP IIb/IIIa Inhibitors in UA/NSTEMI
Trial (IIb/IIIa)
Death / MI at 30 days
Risk Ratio & 95% CI
N
Placebo
2b/3a
(%)
(%)
GUSTO IV
7800
8.0
8.7
PRISM
3232
7.0
5.7
PRISM-Plus
1570
11.9
8.7
PURSUIT
9461
15.7
14.2
PARAGON A
1513
11.7
10.3
PARAGON B
5169
11.4
10.5
12.5
11.3
POOLED
0.91 (0.86, 0.99)
28,745
P=0.015
P=0.339
Breslow-Day
Homogeneity
0.1
Better
1
Worse
10
Boersma et al, Lancet 2002;359:189-1198.
ARR = 1.2%
RRR = 9%
What Does a P(ee) Value of 0.05 Mean?
• ‘Fisherian’ P value of 0.05
is arbitrary and originally
based on n=30!
The plain fact is that in 1925 Ronald Fisher gave
scientists a mathematical machine
turning
“baloney
• for
Always
demand
a P value
into breakthroughs”, and “flukes intooffunding”.
<0.001 for a sample size
Robert
Matthews
> 200
as strong
evidence
against the null hypothesis
of zero difference
Al Feinstein
Disconnect Between Statistical
Significance and Clinical Importance
1
P value

Effect Size  Sample Size
Lack of statistical significance  lack of clinical importance!
Statistical Significance vs. Clinical Importance
Unfractionated Heparin in UA/NSTEMI
Trial
Death/MI
Risk Ratio & 95% CI
N
ASA+UFH ASA
Theroux
243
1.6%
3.3%
RISC
399
1.4%
3.7%
ATACS
214
3.8%
8.3%
Holdright
285
27.3%
30.5%
0%
3%
5.7%
9.6%
7.9%
10.4%
Cohen 1990
Gurfinkel
Overall
69
143
0.67 (0.44-1.02)
P=0.06
1335
0.1
1.0
ASA+UFH Better
10
ASA Better
Oler A et al, JAMA 1996;276:811-15
ARR = 2.5%
RRR = 33%
Statistical Significance vs. Clinical Importance
• MDD (minimum detectable difference, “d”)
- The “minimum difference” the study is powered to detect
- Utilized for sample size estimation
- May or may not reflect a clinically important difference
• MCID (minimum clinically important difference)
The “minimum acceptable difference” to change the behavior
of the clinician, patient, payer or policy maker, given the side
effects, costs and inconveniences of therapeutic interventions
Guideline Criteria for Clinical Importance
Impact of Outcome, Harm, and Cost on MCID
Small
Large
0%
50%
MCID (RRR)
Outcome
severity
Harm
Mortality
Irreversible
morbidity
Reversible
Morbidity
Surrogate
Endpoint
Very low
Low
Moderate
High
Cost
Very low
Low
Moderate
High
Statistical Significance vs. Clinical Importance
MCID Threshold for UA/NSTEMI ACS
“In ACS, a relative reduction of 15% in recurrent clinical events has
recently been considered clinically important (GUSTO I); this level
is far below the perceived threshold that drove the sample size
calculations for clinical trials just a decade ago. As we develop
more incrementally beneficial therapies, it is likely that the
minimally important clinical difference will become even smaller.”
Califf and DeMets
Circulation. 2002;106:1015
Statistical Significance vs. Clinical Importance
Strength of Evidence
MCID
Statistically not significant,
clinically not important
A
Statistically not significant,
may be clinically important
B
Statistically significant,
not clinically important
C
Statistically significant,
may be clinically important
D
Statistically significant,
clinically important
E
MCID = minimal clinically
important difference
= 15% RRD
0.85
1.0
Risk Ratio (95% CI)
Sackett, D
Statistical Significance vs. Clinical Importance
Class I, LOE A Recommendations for UA/NSTEMI
Impact on Death or MI
Intervention
Control
(%)
Rx
(%)
Summary
risk ratio
(95% CI)
P
Value
NNT
(95% CI)
Interpretation of
Confidence Intervals
(MCID = 15% RRR)
Aspirin
(N=2,856)
12.8
5.5
0.43
(0.33-0.56)
<0.01
14
(11-19)
Statistically significant and
clinically important (E)
UFH
(N=1,353)
10.4
7.9
0.67
(0.44-1.02)
0.06
44
(∞-18)
Statistically not significant,
maybe clinically important (B)
Enoxaparin
(Early invasive)
12.8
12.1
0.96
(0.88-1.05)
0.35
171
(∞-59)
Statistically not significant,
clinically not important (A)
Clopidogrel
(CURE)
11.4
9.3
0.82
(0.74-0.92)
<0.01
54
(35-120)
Statistically significant,
maybe clinically important (D)
GP IIb/IIIa
(Early invasive)
14.5
11.8
0.81
(0.70-0.94)
0.007
37
(21-139)
Statistically significant,
maybe clinically important
(D)
Aspirin is the only intervention listed as a performance measure!
Evidence to Guidelines
Lost in Translation
Key Issues for Discussion
•
Establish the scientific evidence
- Appraise and synthesize the evidence
•
Elucidate the clinical context
- Clinical importance vs. statistical significance
- Clinically relevant weighted outcomes
•
Encourage optimal processes of care
- Quality initiatives
- Reimbursement initiatives
Endpoints in Cardiovascular Clinical Trials
MACE vs MICE
Major Adverse Cardiac Events
“Hard” but
infrequent
Death
Cardiac arrest
Large MI
Disabling Stroke
Emergency CABG
Minor Inconvenient Cardiac Events
“Soft” but
prevalent
Silent CK/Tn Release
Restenosis
Reintervention
Recurrent angina
Rehospitalization
Groin hematoma
Cardioprotective Effects of Antihistamines
Means to an End or an End to Means
% patients
Placebo
Antihistamine
Death
Recurrent MI
p < 0.05
Itching
Cardioprotective Effects of Stenting
Clinical Outcomes at 1 Year in Stent PAMI
D/MI/Stroke/TVR
Individual Components
25
30%
Stent (N=452)
P < 0.005
25%
20
20%
PTCA (N=448)
P < 0.0005
15
15%
%
10.7
10
10%
P = 0.07
5.6
5
5%
16.9%
0%
20.9
Stent
(N=449)
P = 0.7
3.1
2.9
2.5
0.5
24.8%
PTCA
(N=444)
P = 0.83
0
Death
MI
0.5
Stroke
TVR
Benefit driven by the “least robust” but the “most prevalent” component
Validity of the Composite Endpoint
• Components should be of comparable frequency
• Components should be of comparable clinical importance
• Components should be comparably responsive to therapy
Montori VM et al. Br Med J 2005; 330:594-596
Cardioprotective Effects of Stenting
Validity of the Composite Endpoint in Stent PAMI
OR (95% CI)
Stent
PTCA
Death
1.81 (0.93-3.53)
5.6%
3.1%
MI
1.17 (0.52-2.65)
2.9%
2.5%
Stroke
0.99 (0.14-7.05)
0.5%
0.5%
0.45 (0.31-0.66)
10.7%
20.9%
0.62 (0.45-0.86)
16.9%
24.8%
Cochran’s Q = 14.64
Hetero P = 0.002
I2 = 80% (46-92%)
TVR
Composite
analysis
0.00
1.00
2.00
3.00
4.00
Odds ratio
Composite: Variable gradient in clinical importance,
frequency and treatment effect across components
Cardioprotective Effects of Stenting
Weighted Analysis of Composite Endpoint
Global P value
1.00
0.90
Weights
0.80
Death = 1
MI = 1
Stroke = 1
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00
Weight of TVR
Composite endpoint becomes significant at a TVR weight of >0.7!
ACC/AHA Guideline Recommendations
Prasugrel During Primary PCI for STEMI
Class I
(Benefit >>> risk)
(Highly recommended)
Class II
IIa
(Benefit >>risk)
(Reasonably
recommended)
Class III
IIb
(Benefit ? risk)
(May be
considered)
(Risk ? Benefit)
(Not recommended)
Level A
(Multiple
randomized
clinical trials)
Level B
(Single randomized
trial or
nonrandomized
studies
Level C
(Consensus
opinion, case
studies, or standard
of care)
60mg prasugrel
load ASAP,
10 mg daily x 12m
Withhold prasugrel
7 days prior to
CABG or surgery
Pts with h/o
TIA or stroke;
active bleeding
Kushner FG, Hand M et al. 2009 Focused Updates, JACC/Circulation 2009
Benefit-Risk Balance in TRITON (All ACS Cohort)
1000 Patients Treated with prasugrel instead of clopidogrel
Prasugrel vs Clopidogrel
Benefit
• 24 endpoints prevented
- 3 CV deaths
- 0 strokes
- 21 nonfatal MIs
- 4 PPMIs
- 17 MI events
- 13 clinically relevant MIs
Risk
• 30 excess TIMI bleeds
- 2 bleeding deaths
- 3 TIMI Major bleeds
- 5 TIMI Minor bleeds
- 20 TIMI Minimal bleeds
or
• 29 excess moderate/severe bleeds
- 2 bleeding deaths
- 9 transfusions
- 6 nonfatal serious bleeds
- 12 nonfatal moderate bleeds
or
• 17 excess serious bleeds
• ? 3-6 excess cancer (1 cancer death)
Judgments about Strength of Recommendation
Prasugrel for Patients with ACS Undergoing PCI
FACTORS
COMMENTS
Balance between desirable
and undesirable effects
“The net benefits are uncertain”
Quality of the evidence
“Quality of the evidence is high.”
Patient values and
preferences
Costs (resource use)
“All patients and care providers
would not accept efficacy-safety
trade-off.” Alternatives available.
“The cost is high for treatment
for long duration.”
Does the evidence favor Class I (benefit >>> risk)
recommendation for prasugrel?
Evidence to Guidelines
Lost in Translation
Key Issues for Discussion
•
Establish the scientific evidence
- Appraise and synthesize the evidence
•
Elucidate the clinical context
- Clinical importance vs. statistical significance
- Clinically relevant weighted outcomes
•
Encourage optimal processes of care
- Quality initiatives
- Reimbursement initiatives
Quality Matters
Linking Guidelines Adherence and Mortality
% In-Hosp Mortality
8
7
5.95
6.31
6
5.16 5.06
5
4.97
4.63
4.16 4.15
4
3
2
Every 10%  in guidelines adherence 
10%  in mortality (OR=0.90, 95% CI: 0.84-0.97)
1
0
<=25%
25 - 50%
50 - 75%
Hospital Composite Quality Quartiles
Adjusted
Unadjusted
Peterson et al, JAMA 2006;295:1863-1912
>=75%
GRACE: Outcome Measures over Time
NSTE ACS
15%
Changes in Clinical Outcomes for
NSTE ACS Patients
•
13.0%
10%
p <.001
6.1%
p = .02 for linear trend
5%
2.9%
0%
2.2%
n = 2213
n =1566
Death
n = 2228
n = 1564
•
Risk-adjusted hospital
deaths declined by 0.7
percentage points (95% CI,
-1.7 to 0.3) in NSTE ACS
patients.
The rate of congestive heart
failure and pulmonary edema
decreased by 6.5% (95% CI,
-8.4 to -4.7).
Heart Failure
Jul -Dec 1999
Jul-Dec 2005
Fox et al. JAMA. 2007; 297:1892-1900
ACC Improvement Initiatives
Continuous Quality Improvement
Translating Science into Practice
Improvement
• D2B
• H2H
• FOCUS
ACT
PLAN
Guidelines/Standards
• Guidelines
• AUC / PM
Education
and Training
Measurement
• NCDR
STUDY
DO
Implementation - “Bridge”
• Quality Practice Assessment
• Clinical Decision Support
• Operation Management Tools
The Role of Evidence-Based Guidelines
in Improving Clinical Practice
Turbocharging the Guidelines
Fuel
Boost
High-quality
evidence
Implementation
Design, process
evaluation
2007 ACC/AHA Guideline Recommendations
Acute Coronary Syndromes
• Number of recommendations: >250
• Number of pages: 157
• Number of figures: 21
• Number of tables: 26
• Last update: 2002
• Writing committee members: 15
• Reviewers: 40 (6 different layers from evaluation to publication)
• Conflict-of-interest disclosure
- Writing committee members: 14/15
- Reviewers: 30/40
J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2007.02.028
Evidence to Guidelines
• Quality
Framework for Refinement
- Rigorous and standardized methodology (GRADE)
- Emphasize clinical importance over statistical significance
- Transparent and explicit benefit-risk assessment
•
Efficiency
- User-friendly and parsimonious (avoid the 160 page report)
•
Timeliness
- Keep pace with advances (annual updates)
•
Dissemination
- Direct clinical relevance (at point of care via EMR)
- Guide and inform clinical practice (performance measures)
- Financial incentives (evidence-based reimbursement)
Evidence to Guidelines
Framework for Refinement
•
•
Firewall between systematic review & guideline development
Multidisciplinary guideline developers: methodologists,
clinical content experts, patient representatives
•
•
•
•
Avoid LOE C recommendations (best suited as “advisories”)
Minimize conflicts of interest (COI) for writers/reviewers
“Zero tolerance” COI policy for chairs
PIs of guideline-relevant trials should only serve as advisors
Evidence-Based Medicine
ACC Improvement Initiatives
• Turbocharging guidelines (18 currently available, 9 in
development, 6 being updated)
• Transform and transfer guidelines at the point of care
- Just in time strategies (Vivisimo, Cardio Compass)
• Appropriate use criteria (Noninvasive imaging, CABG/PCI)
• Quality initiatives (D2B, H2H, FOCUS)
• Registries - NCDR (CathPCI, ICD, CARE, ACTION-GWG,
IMPACT, PINNACLE)
• Physician incentives (PQRI, ACO)
• Patient involvement (CardioSmart)
Framework for Increased Adherence to
Clinical Practice Guidelines and to EBM
• Treat as “guides”, not “rules”
• Patient-specific, not disease-specific
• Pragmatic/assistive, not prescriptive/directive
• Flexible and adapted to local practice
• Based on empirical high-quality evidence, not
“codified” or “filtered” expert clinical opinion
• Drive the standard of care, not be driven by them
• Inform clinical judgment, not replace it
“Evidence-Based” Not “Evidence-Bound”
Three Key Dimensions
Scientific
evidence
Patient
preference
Clinical
Judgment
Complexity of Evidence-Based Guidelines
Illusion of understanding? Illusion of control?
"Yes, I have tricks in my pocket, I have things up my
sleeve. But I am the opposite of a stage magician. He
gives you illusion that has the appearance of truth.
I give you truth in the pleasant disguise of illusion."
Tennessee Williams
(The Glass Menagerie)
Caveats in Interpretation of Meta-analysis
“Although it challenges logic that one could obtain new accurate
information from the quantitative integration of a number of very
diverse studies, the numerous meta-analyses published speak
for themselves. Used in the proper setting, I think they can
make a valuable contribution. The job of the Journal will be to
ensure that those published are in this setting and are
methodologically sound.”
Anthony N DeMaria, MD
Editor-in-Chief, JACC
Has the Journal lived up to its ideals?
J Am Coll Cardiol, 2008; 52:237-238
Turbocharging the Guidelines
ACC Improvement Initiatives
•
•
Separate systematic review from guideline development
Multidisciplinary guideline developers: methodologists,
clinical content experts, patient representatives
•
•
•
•
Avoid LOE C recommendations (best suited as “advisories”)
Minimize conflicts of interest (COI) for writers/reviewers
“Zero tolerance” COI policy for chairs
PIs of guideline-relevant trials should only serve as advisors
Fee for Service or
Fee for Appropriate Service?
What is the Gold Standard?
Do we practice evidence-based medicine or
reimbursement-based medicine?
PCI for Stable CAD
Disconnect Between Policy and Practice
•
Number of PCIs performed for stable CAD
- ~ 500,000/yr at cost of $20K per PCI ($10 billion)
•
Appropriateness of PCI
- Presence of ischemic symptoms
- Objective evidence of ischemia by stress testing
- Failed trial of optimal medical therapy and lifestyle Rx
•
The real-world practice
- 20% of pts referred for PCI are asymptomatic (ACC-NCDR)
- 30-50% of pts have not had a stress test (Topol / Lin et al.);
untold (?60-70%) number of stress tests are “negative”
- 30% of pts not taking anti-ischemic meds (Samuels et al.)
Evidence-Based Reimbursement for Stable CAD
A Financial Incentive for Health Care Reform
• Reimbursement for PCI
- $20K per PCI
•
Score based on appropriateness
- Presence of ischemic symptoms (1/3)
- Objective evidence of ischemia by stress testing (1/3)
- Failed trial of optimal medical therapy and lifestyle Rx (1/3)
•
Sliding-scale reimbursement
- 20% reward for a score of 1
- 20% discount for a score of 2/3
- 60% discount for a score of 1/3
- 100% discount for a score of 0
Diamond and Kaul, Circulation Cardiovasc Qual Outcomes 2009; Archives of Int Med 2009
Evidence-Based Reimbursement for Stable CAD
A Financial Incentive for Health Care Reform
Symptoms
+
+
+
+
Total
Stress
test
+
+
+
+
-
Treatment
Score
Payment
Patients
Reimbursement
+
+
+
+
-
1
2/3
2/3
2/3
1/3
1/3
1/3
0
$24K
$16K
$16K
$16K
$8K
$8K
$8K
0
15,000
85,000
45,000
3,750
255,000
21,250
11,250
63,750
500,000
$0.36B
$1.36B
$0.72B
$0.06B
$2.04B
$0.17B
$0.09B
$0B
$4.8B
• 80% of patients complain of ischemic symptoms
• 50% of patients undergo stress testing; 50% of these are ischemic
• 15% of patients are receiving OMT
13% reduction in caseload and 52% reduction in reimbursement
Statistical Significance vs. Clinical Importance
Class I, LOE A Recommendations for UA/NSTEMI
Impact on Death or MI
Intervention
Control
(%)
Rx
(%)
Summary
risk ratio
(95% CI)
P
Value
NNT
(95% CI)
Interpretation of
Confidence Intervals
(MCID = 15% RRR)
Aspirin
(N=2,856)
12.8
5.5
0.43
(0.33-0.56)
<0.01
14
(11-19)
Statistically significant and
clinically important (E)
UFH
(N=1,353)
10.4
7.9
0.67
(0.44-1.02)
0.06
44
(∞-18)
Statistically not significant,
maybe clinically important (B)
Enoxaparin
(Early invasive)
12.8
12.1
0.96
(0.88-1.05)
0.35
171
(∞-59)
Statistically not significant,
clinically not important (A)
Clopidogrel
(CURE)
11.4
9.3
0.82
(0.74-0.92)
<0.01
54
(35-120)
Statistically significant,
maybe clinically important (D)
GP IIb/IIIa
(Early invasive)
14.5
11.8
0.81
(0.70-0.94)
0.007
37
(21-139)
Statistically significant,
maybe clinically important
(D)
Early statin
(A-to-Z)
12.4
11.1
0.89
(0.74-1.07)
0.21
87
(∞-33)
Statistically not significant,
maybe clinically important (B)