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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 . - PowerPoint PPT Presentation
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Sanjay Kaul, MD, FACCGeorge A. Diamond MD, FACC
Division of CardiologyCedars-Sinai Medical Center and
Geffen School of Medicine at UCLALos Angeles, California
From Clinical Trial Evidence to Practice Guidelines
Lost in Translation
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 EvidenceDesign 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 EvidenceACC/AHA Clinical Practice Guidelines
Class I(“Useful & Effective”)
(Benefit >>> risk)(Highly
recommended)
Class II (“Conflicting Evidence”)
Class III(“Not useful/
effective, may be harmful”)
(No benefit/Harm)(Not recommended)
IIa(Benefit >>risk)
(Reasonably recommended)
IIb(Benefit ? risk)
(May be considered)
Level A(Multiple randomized
clinical trials)
Level B(Single randomized
trial or nonrandomized
studies
Level C(Consensus opinion,
case studies, or standard of care)
Evidence to Guidelines Lost in Translation
Self-evident Truths
• Does empirical evidence trump expert opinion?
Tricoci P et al. JAMA 2009
Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines
Level of Evidence A
4.9
4.9
19
11
9.7
0.3 (1/320)
23.6
6.1
6.4
22.9
12
13.5
15.3
26.4
11.7
0 10 20 30
Radionuclide imaging
PacemakerCABG
PCIVA/SCD
Valvular diseaseUA/NSTEMI
SV arrhythmia
Stable anginaSecondary prevention
PerioperativeSTEMI
PADHeart failure
AF
26.3
58.2
20
47.8
58.5
70.6
29.6
56.5
54.5
8.3
32
47.2
25.1
54.3
58.6
0 10 20 30 40 50 60 70 80
Radionuclide imaging
PacemakerCABG
PCIVA/SCD
Valvular diseaseUA/NSTEMI
SV arrhythmia
Stable anginaSecondary prevention
PerioperativeSTEMI
PADHeart failure
AF
Tricoci P et al. JAMA 2009
Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines
Level of Evidence C
ACC/AHA Clinical Practice Guidelines Paucity of High-Quality Evidence
Class I(Benefit >>> risk)
(Highly recommended)
Class II Class III(Risk ? Benefit)
(Not recommended)
IIa(Benefit >>risk)
(Reasonably recommended)
IIb(Benefit ? risk)
(May be considered)
Level A(Multiple
randomized clinical trials)
19% based on high-level evidence
41% of guidelines are
based on Class II recommendations
(”uncertain evidence”)Level B
(Single randomized trial
or 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
Recommendations are largely developed from lower levels of evidence or expert opinion. “Exercise caution when considering recommendations not supported by solid evidence”
“…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
Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines
Caveat Emptor, Caveat Lector
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)
Class II Class III(Risk ? Benefit)
(Not recommended)
IIa(Benefit >>risk)
(Reasonably recommended)
IIb(Benefit ? risk)
(May be considered)
Level A(Multiple
randomized clinical trials)
12% based on high-level evidence
50% of guidelines are
based on Class II recommendations
(“conflicting evidence”)Level B
(Single randomized trial
or nonrandomized studies
Level C(Consensus
opinion, case studies, or
standard of care)
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 evidence-1
Peter McCullochThe Lancet, 2004;363;9004
vehemence eminence2
• 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
Evidence to Guidelines Lost in Translation
Key Issues for Discussion
• Effect size- Absolute risk difference (NNT or NNH) - Relative risk difference
Risk ratioOdds ratioHazard ratio
• Statistical certainty/precision- Hypothesis testing (P value)- Estimation (confidence interval)
• ? Clinical importance
Little or no explicit guidance
ACC/AHA Clinical Practice GuidelinesMetrics for Assessing Strength of Evidence
1
P value Effect Size Sample Size
Statistical significance Clinical importance!
Disconnect Between Statistical Significance and Clinical Importance
Boersma et al, Lancet 2002;359:189-1198.
GUSTO IV
PRISM
PRISM-Plus
PURSUIT
PARAGON A
PARAGON B
POOLED
Trial (IIb/IIIa) Placebo 2b/3a
7800
3232
1570
9461
1513
5169
28,745
N
8.0
7.0
11.9
15.7
11.7
11.4
12.5
8.7
5.7
8.7
14.2
10.3
10.5
11.3
Better Worse0.1 1 10
Death / MI at 30 daysRisk Ratio & 95% CI (%) (%)
0.91 (0.86, 0.99)P=0.015
P=0.339Breslow-DayHomogeneity
ARR = 1.2%RRR = 9%
Statistical Significance vs. Clinical ImportanceGP IIb/IIIa Inhibitors in UA/NSTEMI
What Does a P(ee) Value of 0.05 Mean?
• ‘Fisherian’ P value of 0.05 is arbitrary and originally based on n=30!
• Always demand a P value of <0.001 for a sample size > 200 as strong evidence against the null hypothesis of zero difference
Al Feinstein
The plain fact is that in 1925 Ronald Fisher gave scientists a mathematical machine for turning “baloney into breakthroughs”, and “flukes into funding”.
Robert Matthews
1
P value Effect Size Sample Size
Lack of statistical significance lack of clinical importance!
Disconnect Between Statistical Significance and Clinical Importance
Oler A et al, JAMA 1996;276:811-15
0.1 1.0 10
Risk Ratio & 95% CI ASA+UFH ASATrial NTheroux 243
RISC 399
ATACS 214
Holdright 285
Cohen 1990 69
Gurfinkel 143
1.6% 3.3%
1.4% 3.7%
3.8% 8.3%
27.3% 30.5%
0% 3%
5.7% 9.6%
ASA+UFH Better ASA Better
Overall 1335 7.9% 10.4%0.67 (0.44-1.02)
P=0.06
Death/MI
ARR = 2.5%RRR = 33%
Statistical Significance vs. Clinical ImportanceUnfractionated Heparin in UA/NSTEMI
• MDD (minimum detectable difference, “”)- 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
Statistical Significance vs. Clinical Importance
Guideline Criteria for Clinical ImportanceImpact of Outcome, Harm, and Cost on MCID
Very low Low Moderate HighHarmVery low Low Moderate HighCost
Mortality Irreversiblemorbidity
ReversibleMorbidity
SurrogateEndpoint
Outcomeseverity
Small Large
MCID (RRR)0% 50%
Statistical Significance vs. Clinical ImportanceMCID 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 DeMetsCirculation. 2002;106:1015
1.0
Risk Ratio (95% CI)
0.85
MCID
Statistically significant, clinically important
Statistically not significant, may be clinically important
Statistically significant, not clinically important
Statistically not significant, clinically not important A
B
C
D
E
Statistically significant, may be clinically important
MCID = minimal clinically important difference= 15% RRD
Sackett, D
Statistical Significance vs. Clinical ImportanceStrength of Evidence
Intervention Control(%)
Rx(%)
Summary risk ratio (95% CI)
PValue
NNT(95% CI)
Interpretation ofConfidence 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)
Statistical Significance vs. Clinical ImportanceClass I, LOE A Recommendations for UA/NSTEMI
Impact on Death or MI
Aspirin is the only intervention listed as a performance measure!
• 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
Evidence to Guidelines Lost in Translation
Key Issues for Discussion
Endpoints in Cardiovascular Clinical TrialsMACE vs MICE
DeathCardiac arrestLarge MIDisabling Stroke Emergency CABG
Major Adverse Cardiac Events
“Hard” but infrequent Silent CK/Tn Release
RestenosisReinterventionRecurrent anginaRehospitalizationGroin hematoma
Minor Inconvenient Cardiac Events
“Soft” but prevalent
Cardioprotective Effects of AntihistaminesMeans to an End or an End to Means
PlaceboAntihistamine
% p
atie
nts
Death Recurrent MI Itching
p < 0.05p < 0.05
Cardioprotective Effects of StentingClinical Outcomes at 1 Year in Stent PAMI
16.9% 24.8%0%
5%
10%
15%
20%
25%
30%D/MI/Stroke/TVR
P < 0.005
Stent(N=449)
PTCA(N=444)
2.9 2.5
P = 0.7
MI
10.7
20.9
P < 0.0005
TVR
5.63.1
0
5
10
15
20
25Stent (N=452)
PTCA (N=448)
P = 0.07
Death
%
Individual Components
0.5 0.5
P = 0.83
Stroke
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
Compositeanalysis
0.00 1.00 2.00 3.00 4.00
TVR
Stroke
MI
Death
Odds ratio
1.81 (0.93-3.53)
1.17 (0.52-2.65)
0.99 (0.14-7.05)
0.45 (0.31-0.66)
0.62 (0.45-0.86)
OR (95% CI)
5.6%
2.9%
0.5%
10.7%
16.9%
Stent
3.1%
2.5%
0.5%
20.9%
24.8%
PTCA
Cardioprotective Effects of Stenting Validity of the Composite Endpoint in Stent PAMI
Cochran’s Q = 14.64Hetero P = 0.002I2 = 80% (46-92%)
Composite: Variable gradient in clinical importance, frequency and treatment effect across components
Cardioprotective Effects of StentingWeighted Analysis of Composite Endpoint
Weight of TVR
Glo
bal P
val
ueWeightsDeath = 1
MI = 1Stroke = 1
0.000.100.200.300.400.500.600.700.800.901.00
0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00
Composite endpoint becomes significant at a TVR weight of >0.7!
Class I(Benefit >>> risk)
(Highly recommended)
Class II Class III(Risk ? Benefit)
(Not recommended)IIa(Benefit >>risk)
(Reasonably recommended)
IIb(Benefit ? risk)
(May be considered)
Level A(Multiple
randomized clinical trials)
Level B(Single randomized
trial or nonrandomized
studies
60mg prasugrelload ASAP, 10 mg daily x 12m
Level C(Consensus
opinion, case studies, or standard
of care)
Withhold prasugrel 7 days prior to CABG or surgery
Pts with h/o TIA or stroke; active bleeding
ACC/AHA Guideline RecommendationsPrasugrel During Primary PCI for STEMI
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 ClopidogrelBenefit
• 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 RecommendationPrasugrel for Patients with ACS Undergoing PCI
FACTORS COMMENTSBalance between desirableand undesirable effects “The net benefits are uncertain”
Quality of the evidence “Quality of the evidence is high.”
Patient values andpreferences
“All patients and care providerswould not accept efficacy-safetytrade-off.” Alternatives available.
Costs (resource use) “The cost is high for treatmentfor long duration.”
Does the evidence favor Class I (benefit >>> risk)recommendation for prasugrel?
• 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
Evidence to Guidelines Lost in Translation
Key Issues for Discussion
Quality MattersLinking Guidelines Adherence and Mortality
Peterson et al, JAMA 2006;295:1863-1912
5.955.16 4.97
4.165.06
4.634.15
6.31
012345678
<=25% 25 - 50% 50 - 75% >=75%
Hospital Composite Quality Quartiles
% In
-Hos
p M
orta
lity
Adjusted Unadjusted
Every 10% in guidelines adherence 10% in mortality (OR=0.90, 95% CI: 0.84-0.97)
• 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).
2.9%
13.0%
2.2%
6.1%
0%
5%
10%
15%
Death Heart FailureJul -Dec 1999 Jul-Dec 2005
Changes in Clinical Outcomes for NSTE ACS Patients
n = 2213
p = .02 for linear trend
p <.001
n =1566 n = 2228 n = 1564
GRACE: Outcome Measures over TimeNSTE ACS
Fox et al. JAMA. 2007; 297:1892-1900
ACC Improvement InitiativesContinuous Quality Improvement
Translating Science into Practice
Improvement• D2B• H2H• FOCUS
Measurement• NCDR
Implementation - “Bridge”• Quality Practice Assessment• Clinical Decision Support• Operation Management Tools
Guidelines/Standards• Guidelines• AUC / PM
PLAN
DO
STUDY
ACT
Education and Training
FuelHigh-quality
evidence
BoostImplementation
Design, process evaluation
The Role of Evidence-Based Guidelinesin Improving Clinical Practice
Turbocharging the Guidelines
• 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
2007 ACC/AHA Guideline Recommendations Acute Coronary Syndromes
• Quality- 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 GuidelinesFramework 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 to GuidelinesFramework for Refinement
Evidence-Based MedicineACC 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)
• 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
Framework for Increased Adherence to Clinical Practice Guidelines and to EBM
ClinicalJudgment
“Evidence-Based” Not “Evidence-Bound”Three Key Dimensions
Scientificevidence
Patient preference
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.”
J Am Coll Cardiol, 2008; 52:237-238
Anthony N DeMaria, MDEditor-in-Chief, JACC
Has the Journal lived up to its ideals?
• 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
Turbocharging the GuidelinesACC Improvement Initiatives
Do we practice evidence-based medicine or reimbursement-based medicine?
Fee for Service or Fee for Appropriate Service?
What is the Gold Standard?
PCI for Stable CADDisconnect 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.)
• 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
Evidence-Based Reimbursement for Stable CADA Financial Incentive for Health Care Reform
Diamond and Kaul, Circulation Cardiovasc Qual Outcomes 2009; Archives of Int Med 2009
Symptoms Stresstest
Treatment Score Payment Patients Reimbursement
+ + + 1 $24K 15,000 $0.36B+ + - 2/3 $16K 85,000 $1.36B+ - + 2/3 $16K 45,000 $0.72B- + + 2/3 $16K 3,750 $0.06B+ - - 1/3 $8K 255,000 $2.04B- + - 1/3 $8K 21,250 $0.17B- - + 1/3 $8K 11,250 $0.09B- - - 0 0 63,750 $0B
Total 500,000 $4.8B
Evidence-Based Reimbursement for Stable CADA Financial Incentive for Health Care Reform
• 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
Intervention Control(%)
Rx(%)
Summary risk ratio (95% CI)
PValue
NNT(95% CI)
Interpretation ofConfidence 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)
Statistical Significance vs. Clinical ImportanceClass I, LOE A Recommendations for UA/NSTEMI
Impact on Death or MI