Temporal Trends in Clinical
Trials of NSTE ACS over 15
Years
Mark Y. Chan, Jie-Lena Sun, L. Kristin Newby,
Harvey D. White, David J. Moliterno, Pierre
Théroux, E. Magnus Ohman, Karen S. Pieper,
Robert P. Giugliano, Paul W. Armstrong, Robert
M. Califf, Frans Van de Werf,
Robert A. Harrington
Funding Sources
• This work was supported by the Merck/Schering-Plough
Alliance. Merck/ Schering-Plough was not involved in the
design and conduct of the study, or the collection,
management, analysis, and interpretation of the data.
• The individual trials were funded by the following
sponsors: GUSTO IIb: Ciba–Geigy, (Summit, N.J.),
Boehringer Mannheim (Indianapolis), and Guidant
(Redwood City, Calif.), PURSUIT: COR Therapeutics and
Schering-Plough Research Institute, PARAGON-A:
Hoffman La-Roche (Basel, Switzerland), PARAGON-B:
F. Hoffman-La Roche Ltd. (Basel, Switzerland), PRISM:
Merck & Co, Inc., PRISM-PLUS: Merck & Co, Inc.,
GUSTO IV ACS: Eli-Lilly and Co. Inc (Indianapolis, IN),
SYNERGY: Sanofi-Aventis (Paris, France) Early ACS:
Schering-Plough (Kenilworth, NJ).
Disclosures
HD White: grants from Schering-Plough, Merck; DJ
Moliterno: grants, consulting from Schering-Plough; P
Théroux: grants, speaker fees from Schering-Plough; RP
Giugliano: grants, advisory board, honoraria from
Schering-Plough, Merck; PW Armstrong: consulting for
Merck Frosst Canada Ltd, grants from Schering-Plough,
Merck; F Van de Werf: grants from Schering-Plough,
advisory board, speakers fee from Schering-Plough,
Merck. MY Chan, JL Sun, KS Pieper: none. Disclosures
for LK Newby, EM Ohman, RM Califf, & RA Harrington
may be viewed at
http://www.dcri.duke.edu/research/coi.jsp.
Background
•
•
•
•
•
Over the last 2 decades, phase III randomized controlled trials (RCT)
of antithrombotic therapy in non-ST-segment elevation acute
coronary syndromes (NSTE ACS) have defined contemporary
treatment strategies for NSTE ACS.
Concurrently, in part due to these and other trials, standard therapy
for NSTE ACS has evolved and population characteristics and trial
inclusion criteria have reflected progressively higher risk.
We described temporal trends in study population risk and
background therapy and outcomes in large randomized trials of
antithrombotic therapy in ACS conducted consecutively over a 15year period.
We also described the relationships between baseline risk profiles
and background treatment trends and trends in clinical outcomes
over this 15-year period.
We hypothesized that, in a large series of consecutive NSTE ACS
clinical trials, changes in risk profiles of study subjects would be
counterbalanced by use of evidence-based background therapy and
result in similar clinical outcomes over time.
Methods
•
•
•
•
•
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We used data from 9 consecutive phase III, international, RCTs of
antithrombotic therapy in NSTE ACS coordinated by the DCRI from
1994 to 2009.
Data from GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B,
PRISM, PRISM-PLUS, GUSTO IV, SYNERGY and EARLY ACS were
merged at the patient level.
27,550 (47%) were diagnosed with unstable angina and 31,072
(53%) were diagnosed with NSTEMI.
Baseline characteristics, discharge medicines, and in-hospital, 30day, and 6-month outcomes were trended across 15 years.
Time trends were analyzed across 5 equal 3-year time periods, to
maintain sample size homogeneity across comparison groups.
Time trends were tested at a significance level of α=0.05.
Year of Subject Randomization in Each
Trial
Time Trends in Population Characteristics
Time Trends in Background Pharmacotherapy
Pre-randomization Pharmacotherapy: 15-year Trend
%
100
80
Aspirin
60
Thienopyridine
ACE-Inh
40
β-blocker
20
Statin
0
1994-1996 1997-1999 2000-2002 2003-2005 2006-2008
Year
Inhospital Pharmacotherapy: 15-year Trend
%
100
80
Aspirin
60
Thienopyridine
ACE-Inh
40
β-blocker
20
Statin
0
1994-1996 1997-1999 2000-2002 2003-2005 2006-2008
Year
Discharge Pharmacotherapy: 15-year Trend
%
100
80
Aspirin
60
Thienopyridine
ACE-Inh
40
β-blocker
20
Statin
0
1994-1996 1997-1999 2000-2002 2003-2005 2006-2008
Year
Time Trends in Outcomes
Inhospital Bleeding: 15-Year Trend
35
30
25
Mild bleeding
%
20
Moderate bleeding
15
Severe bleeding
10
5
0
1994-1996
1997-1999
2000-2001
Year
2003-2005
2006-2008
Inhospital, 30-day and 6-month Death: 15-Year Trend
7
6
%
5
Inhospital death
30-day death
6-month death
4
3
2
1
0
1994-1996 1997-1999 2000-2002 2003-2005 2006-2008
Year
%
Thirty-day Death or MI: 15-year Trend
16
14
12
10
8
6
4
2
0
30-day death
30-day MI
30-day death or MI
19941996
19971999
20002002
Year
20032005
20062008
Invasive Management: 15-year Trend
100
Cardiac catheterization
%
80
60
Percutaneous coronary
intervention
40
Coronary artery bypass
grafting
20
0
19941996
19971999
20002002
Year
20032005
20062008
Conclusions
•
This analysis of 58,771 subjects from 9 consecutive
large multinational phase III RCTs demonstrates an
overall increase in subject risk and a rapid increase in
the use of evidence-based background
pharmacotherapies post-randomization and at
discharge.
• These trends were associated with a consistent decline
in early and late mortality over 15 years.
• Non-fatal MI rates increased over the 15-year
observation period
• Declining mortality rates and increasing non-fatal MI
rates, the latter possibly driven by more sensitive cardiac
biomarkers, greater procedural use andchanges in MI
definition, warrant consideration of novel study designs
and reassessment of MI adjudication strategies in future
RCTs.