Transcript How the overall results of randomized clinical trials can

Treatment of acute
(cardio- and cerebro-)
vascular syndromes
David Kent, MD, MS
Institute for Clinical Research and Health Policy Studies
Tufts-New England Medical Center, Boston
• Average results of clinical trials do not
apply to all patients.
• Even in trials with well-defined
inclusion/exclusion criteria, there is often
considerable variation in outcome-risk.
Avg mortality risk = ~ 1%
Avg mortality risk = ~ 16%
Avg mortality risk = ~ 1%
Summary result reflects arithmetic mean
Summary result reflects arithmetic mean
Typical “median-risk” patient
The Thrombolytic Predictive
Instrument
• Predicts patient-specific outcomes in acute
myocardial infarction in real time.
• Based on several validated logistic
regression equations.
Easily obtainable variables
• Clinical
–
–
–
–
–
age
systolic blood pressure
diabetes
thrombolytic therapy
time from symptom onset
to ECG
• Electrocardiographic
– right bundle branch block
– heart rate
– number of leads with ST
segment elevation
– amount of ST-segment
elevation
– leads with abnormal qwaves and no ST elevation
– infarct location
tPA versus Streptokinase in STEMI
GUSTO
• Mortality with t-PA: 6.3%
• Mortality with streptokinase: 7.3%
• Thrombolytic-related brain hemorrhages:
– t-PA: 0.72%
– SK: 0.52%
• Cost:
– t-PA: $2,750
– SK: $320
Hypothesis
• Most of the incremental benefit of t-PA
compared to SK can be obtained by treating
a subgroup of high-risk (high-benefit)
patients.
Distribution of Predicted Incremental Mortality Benefit in the
GUSTO Population for t-PA vs. Streptokinase
Absolute Mortality Benefit
(in percentage points)
6%
5%
4%
3%
2%
1%
0%
0
10
20
30
40
50
60
Percentile Mortality Benefit
70
80
90
100
Mortality in GUSTO Trial
by Quartile of Predicted Mortality Benefit
16%
14%
12%
Mortality
10%
SK
t-PA
8%
6%
4%
2%
0%
1
2
3
Quartile of Predicted Mortality Benefit
4
Thrombolytic-related ICH-risk in
Myocardial Infarction
–
–
–
–
–
–
–
(Gurwitz et al)
Age
sex,
race (white, black or other)
history of prior stroke
systolic blood pressure
diastolic blood pressure
interaction term: age* gender * history of prior
stroke
Distribution of Incremental Composite Benefit in the GUSTO
Population for t-PA vs. Streptokinase
Absolute Composite Benefit
(in percentage points)
6%
5%
4%
3%
2%
1%
0%
0
10
20
30
40
50
60
70
-1%
Percentile Composite Benefit
80
90
100
Composite Outcomes (Mortality or ICH) in GUSTO
by Quartile of Predicted Benefit
14%
12%
Mortality or ICH
10%
8%
SK
t-PA
6%
4%
2%
0%
1
2
3
Qyartile of Predicted Benefit
4
Distribution of Marginal Cost-Effectiveness of t-PA Relative to
Streptokinase
Cost per Year of Life Saved (dollars)
300000
250000
200000
150000
100000
50000
0
0
10
20
30
40
50
60
70
80
90
100
Percentile Composite Benefit (in Life Years, including mortality and ICH)
Conclusion
• Population-wide treatment of STEMI
patients with tPA is effective and costeffective.
Conclusion
• Population-wide treatment of STEMI
patients with tPA is effective and costeffective.
• For many patients tPA is highly unlikely to
provide incremental mortality benefit (and it
may cause net harm for some).
Conclusion
(methodology)
• Conventional sub-group analysis was
unable to identify patients most likely or
unlikely to benefit from t-PA.
PCI versus thrombolysis in STEMI
• Primary PCI yields superior outcomes to
thrombolytic therapy in acute myocardial
infarction.
• Composite outcome: death, non-fatal
reinfarction and stroke.
• 22 trial meta-analysis (Lancet, 2003):
– mortality: 5% vs 7%; p=0.0003
Methods
• We modified the TPI to predict--in
individual patients--the incremental
mortality benefit of primary PCI compared
to thrombolytic therapy.
Methods
(cont’d)
• Developmental Database
– 3006 patients with complete data
• 1378 received primary angioplasty;
• 1628 received thrombolytic therapy.
• Validation Dataset
– Atlantic Cardiovascular Patient Outcomes
Research Team (C-PORT) trial
Results: Model Validation
(C-PORT)
ROC Area
0.87
Predicted Mortality
Observed Mortality
Thrombolytic Therapy
6.3%
6.0% (95% CI: 2.6% - 9.5)
PTCA
4.5%
3.9% (95% CI: 0.8% - 6.9%)
Distribution of Predicted Mortality Benefit
for PTCA at 90 minutes compared to Thrombolytic Therapy at 45 minutes
20%
Absolute Mortality Benefit
15%
10%
5%
0%
0
10
20
30
40
50
60
-5%
Percentile Rank of Benefit
C-PORT (validation) dataset
70
80
90
100
Predicted versus Observed
Benefits
C-PORT Trial
Thrombolytic
Therapy
PCI
Predicted
tile of Predicted Mortality Benefit
Mortality Benefit* 6 Week Mortality 6 Week Mortality
Tertile of most benefit of PCI
Tertile of least benefit of PCI
Mean
Mean Sum N Mean Sum
N
4.8%
15.0%
9 60 9.6%
5
52
0.0%
1.6%
1 62 0.0%
0
51
-0.9%
1.7%
1 60 1.9%
1
52
DANAMI-2
DANAMI-2
Treatment of ACS
ACS
• Greater relative and absolute benefit found
in TIMI-high risk patients
– the low molecular weight heparin enoxaparin
(compared to unfractionated heparin),
– the glycoprotein IIb/IIIa inhibitor tirofiban
– an early invasive strategy (compared to
conservative approach)
Thrombolysis in Acute Stroke
The NINDS tPA trial
• The NINDS tPA study demonstrated that tPA
improved outcomes in patients with stroke treated
within 3 hours of symptom onset.
• Absolute benefit was from 11% to 15%
– likelihood of a normal or near-normal 90-day outcome
• Despite a 6% increase in the risk of intracranial
hemorrhage.
• Based on these results, FDA approved the
use of tPA in stroke, in the 0 to 3 hour time
window, in 1996.
• Currently, about 2% of patients with acute
stroke receive thrombolytic therapy.
Other trials
• ECASS 1
– dose: 1.1 mg/kg
– time window 0 to 6 hours
• ECASS 2
– time window 0 to 6 hours
– primary outcome: mRS < 2
• ATLANTIS A
– time window 0 to 6 hours
• ATLANTIS B (after NINDS completed)
– time window: 3 to 5 hours (mostly)
Overall Outcomes in ATLANTIS B Trial
70%
60%
50%
Proportion of patients 40%
with good outcomes
30%
20%
10%
0%
NIH
Barthel
Modified
Rankin
Glasgow
placebo (n=306)
34%
55%
41%
46%
rt-PA (n=307)
35%
54%
42%
46%
Global Outcome: p=0.70
Thrombolytic-related ICH-risk in
Myocardial Infarction
–
–
–
–
–
–
–
(Gurwitz et al)
Age
sex,
race (white, black or other)
history of prior stroke
systolic blood pressure
diastolic blood pressure
interaction term: age* gender * history of prior
stroke
Rate of intracranial hemorrhage
with thrombolytic therapy
OUTCOME
symptomatic ICH
low risk (n=90)
med/high -risk (n=196)
2.2 %
9.2 %
Outcomes: Low-risk Group in ATLANTIS B Trial
70%
60%
50%
Proportion of patients
with good outcomes 40%
30%
20%
10%
0%
NIH
Barthel
Modified
Rankin
Glasgow
placebo (n=105)
30%
59%
37%
41%
rt-PA (n=90)
39%
64%
49%
49%
Global Outcome: p=0.10
Treatment-by-risk: p=0.03
Summary
• On average, tPA does not benefit stroke
patients overall when given after 3 hours.
• However, individual risk-benefit patient
profiling suggests that more than half of
patients might benefit from therapy.
Summary
• Average results of clinical trials do not apply to all
patients in the trial.
• Conventional analysis of trials can lead harmfully
to both over and under-treatment of important
subgroups.
• Combining variables into risk scores predicting
outcome risk or treatment-related harm can
uncover patients with dramatically different riskbenefit treatment profiles.