Transcript Slide 1

Comparison of ACCORD trial outcomes with
outcomes estimated from modelled and metaanalysis studies
Volker Foos1, Adam Lloyd2, Nick Freemantle3, David Grant2,
William Herman4.
1IMS
Health, Basel, Switzerland, 2IMS Health, London, UK, 3University College
London, London, UK, 4University of Michigan, Ann Arbor, MI, USA
EASD ORAL PRESENTATION– 13th September 2011
Session: OP 01 Assessing cardiovascular risk
Presentation number: 3
Foos et al, EASD, Lisbon, 13 September 2011
Background
The ACCORD trial reported higher mortality in type 2
diabetes patients treated with intensive glycemic control
• The ACCORD trial1
− Randomized controlled study including 10251 patients
− Purpose to investigate whether intensive therapy to target normal
glycated hemoglobin levels would reduce cardiovascular events in
patients with type 2 diabetes who had either established
cardiovascular disease or additional cardiovascular risk factors.
Treatment Targets:
Intensive glycemic control:
Standard Treatment:
HbA1c < 6%
HbA1c between 7% and 7.9%
Effects of Intensive Glucose Lowering in Type 2 Diabetes, The Action to Control Cardiovascular Risk in Diabetes
Study Group, N Engl J Med June 2008
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Background
The ACCORD trial findings in detail
Findings after 3.5 years of follow up
•All cause mortality was found to be increased in the intensified treatment arm
with an hazard ratio of 1.22
•Hypoglycemia as well as weight gain was increased with intensive treatment
•major cardiovascular events were not significantly reduced
Foos et al, EASD, Lisbon, 13 September 2011
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Background
Findings of the ACCORD trial contradict with earlier
landmark studies
• Results of ACCORD suggest that intensive glucose lowering in highrisk patients with type 2 poses a harm that was not recognized to
this stage.
• These findings contradict with earlier landmark investigations
such as the UKPDS (T2D) and the DCCT/EDIC (T1D) which have
shown that intensive blood glucose control can substantially lower
the risk of diabetes complications and reduce the long-term risk of
developing cardiovascular disease.
• Although the effects were found to be significant, the underlying
causes for the increased mortality rates are yet not fully understood
and a debate has started about the reasons for the these findings
and their implications to current treatment guidelines.
Foos et al, EASD, Lisbon, 13 September 2011
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Materials and methods
The purpose of this investigation was to put the ACCORD
findings into context by comparing them to outcomes of other
data sources
• To compare ACCORD findings to a recently conducted random
effects meta-analysis including data from ACCCORD, ADVANCE
and VADT
• To compare ACCORD findings to etimates of a well established and
validated computer simulation model for type 2 diabetes (IMS
CORE Diabetes Model)
• Modelling approach
− Cardiovascular risk scores were calculated on the basis of UKPDS data2
− Two distinct approaches were compared
Standard approach – Continuous and unlimited risk
decrease for glucose lowering
Modified approach – HbA1c related CV risk reductions
were limited to values > 7%
A model to estimate the lifetime health outcomes of patients with Type 2 diabetes: the UKPDS Outcomes Model
(UKPDS no. 68), P. M. Clarke et al. , Diabetologia (2004)
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Materials and methods
Comparison of end points
Relative risk scores for intensified versus standard treatment
were compared for the below listed end points:
Meta Analysis
End Points (RR)
•Non fatal MI
ACCORD
•Non fatal stroke
•Heart failure
•All cause mortality
Model 1
Restriction of additional
risk decrease below 7%
Model 2
No Restriction of additional
risk decrease
Foos et al, EASD, Lisbon, 13 September 2011
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Results
The random effects Meta Analysis included data from the ACCORD,
ADVANCE and VADT trials
All cause mortality (Odds ratios and 95% CI)
Foos et al, EASD, Lisbon, 13 September 2011
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Results
The random effects Meta Analysis included data from the ACCORD,
ADVANCE and VADT trials
Myocardial Infarction (Odds ratios and 95% CI)
Foos et al, EASD, Lisbon, 13 September 2011
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Results
The random effects Meta Analysis included data from the ACCORD,
ADVANCE and VADT trials
Stroke (Odds ratios and 95% CI)
Foos et al, EASD, Lisbon, 13 September 2011
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Results
The random effects Meta Analysis included data from the ACCORD,
ADVANCE and VADT trials
Heart Failure (Odds ratios and 95% CI)
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Results
Comparison of CVD endpoints and mortality – ACCORD vs.
meta-analysis and model projections
RR for intensive versus standard glucose lowering - ACCORD vs. Pooled estimates
and modelling projections
Confidence intervals from ACCORD trial
1.60
ACRD
1.50
1.40
RR from meta analysis
1.30
1.27
1.23
RRR
1.20
1.10
1.07
Model 2 - CV risk adj. for
HbA1c >= 7%
0.95
0.94
Model 1 - standard
1.10
1.03
1.00
0.97
0.97
0.93
0.91
0.90
0.86
0.82
0.79
0.76
0.80
0.83
0.70
0.60
0.5
MI
1.5
Stroke
2.5
HF
3.5
All cause
death
4.5
Model
RR predictions
of all cause for
mortalty
non fatal
for MI,
intensively
non fatal
treated
strokepatients
and heart
in ACCORD
failure didwas
lie
within
significantly
the 95%
higher
CIs than
derived
model
from
projections
ACCORD.
Foos et al, EASD, Lisbon, 13 September 2011
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Results
Comparison of CVD endpoints and mortality – ACCORD vs.
meta-analysis and model projections
RR for intensive versus standard glucose lowering - ACCORD vs. Pooled estimates
and modelling projections
Confidence intervals from pooled estimates
1.60
ACRD
1.50
1.40
RR from meta analysis
1.30
1.27
1.23
RRR
1.20
1.10
1.07
Model 2 - CV risk adj. for
HbA1c >= 7%
0.95
0.94
Model 1 - standard
1.10
1.03
1.00
0.97
0.97
0.93
0.91
0.90
0.86
0.82
0.79
0.76
0.80
0.83
0.70
0.60
0.5
MI
1.5
Stroke
2.5
HF
3.5
All cause
4.5
death
Adjusting
the model
so continuing
reduce Hba1c
below 7%
causes no
Model
outcomes
fell withintoconfidence
intervals
predicted
by further
the metareduction in CV risk brought the model estimates closer to ACCORD
findings.
analysis for all events.
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Conclusion
Findings of the ACCORD trial contradict with earlier
landmark studies
• Relative risk of all cause mortality in ACCORD was significantly
different from that modelled based on previous data.
• This difference
− was not seen in other endpoints,
− was not consistent across recent studies,
− and was not fully explained by hypothesising a lower limit of 7% for
HbA1c benefit.
• Observed mortality effects in the ACCORD trial may be related to
factors other than glucose lowering.
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Thank You!
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