JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 66, NO. 5, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2015.06.024
EDITORIAL COMMENT
The Early Invasive Strategy in
Acute Coronary Syndromes
Should the Guideline Recommendations Be Revisited?*
Manesh R. Patel, MD, E. Magnus Ohman, MD
T
he early invasive strategy with cardiac cathe-
Coronary Events) risk score or by other risk character-
terization within 72 h of onset of symptoms
istics. The majority of the trials also have reported
has now become standard-of-care in the ma-
longer-term outcomes data, but none of them have
jority of countries around the world for patients with
acute coronary syndromes (ACS). It is a Class 1B
recommendation in the latest American College of
Cardiology/American
practice
In this issue of the Journal, Henderson et al. (7)
report on the long-term mortality outcomes of the
ACS and a Level 1A recommendation from the Euro-
RITA-3 trial at 10 years. This is a fascinating evalua-
pean Society of Cardiology (1,2). This very firm foun-
tion of long-term data that is so rarely possible, but
dation
by
it is facilitated by linking a national registry in the
several landmark studies carried out in the late
United Kingdom with a clinical trial cohort. The
1990s and the early 2000s (3–6). In aggregate, these
authors had previously reported the 5-year follow-up
prospective randomized trials provided ample evi-
data from the RITA-3 trial (8). In the current report,
dence that major cardiovascular endpoints such as
the investigators use the office of national statistics to
death and myocardial infarction were reduced with
obtain all-cause mortality from 5 to 10 years following
recommendation
Association
SEE PAGE 511
guidelines for non–ST-segment elevation (NSTE)
of
Heart
reported beyond 5 years.
was
established
an invasive strategy over a selective invasive strat-
the original randomization. They find that the all-
egy. The RITA-3 (Third Randomised Intervention
cause mortality reduction of 24% seen at 5 years has
Treatment of Angina) randomized trial provided a
slowly dissipated by 10 years, with no statistical sig-
unique insight into this, because the trial also demon-
nificance. The authors further stratify the results by
strated reduced all-cause mortality at 5 years.
the post-discharge GRACE score and find no clear
Furthermore, when these trials were combined into
treatment effect by low-, intermediate-, or high-risk
a patient-level meta-analysis in patients who were
categories. They also perform a multivariable model
risk stratified, it became apparent that this strategy
that identifies age, prior myocardial infarction or
was most beneficial in the high-risk patient cohorts,
heart failure, and extent of coronary disease as
either defined by the GRACE (Global Registry of Acute
important predictors of long-term mortality, but not
the randomization strategy. Given these results, the
authors conclude that we require further clinical
*Editorials published in the Journal of the American College of Cardiology
trials of contemporary interventional strategies in
reflect the views of the authors and do not necessarily represent the
patients with NSTE-ACS. These conclusions will likely
views of JACC or the American College of Cardiology.
From the Division of Cardiovascular Medicine, Duke Heart Center, Duke
Clinical Research Institute, Duke Medicine, Durham, North Carolina.
give clinicians and guideline committees pause as
they consider the current recommended strategies for
Dr. Ohman has received research grants from Daiichi-Sankyo, Eli Lilly &
management of patients with NSTE-ACS. To under-
Co., Gilead Sciences, and Janssen Pharmaceuticals; and has served as a
stand the results, we must consider both what we do
consultant for Abiomed, AstraZeneca, Biotie, Boehringer Ingelheim,
Daiichi-Sankyo, Eli Lilly & Co., Faculty Connection, Gilead Sciences,
Janssen Pharmaceuticals, Merck, Stealth Peptides, The Medicines Company, and WebMD. Dr. Patel has reported that he has no relationships
relevant to the contents of this paper to disclose.
know for certain from the RITA-3 investigators’ report
and the limitations of the study.
What remain unknown are the long-term effects of
a routine invasive strategy on recurrent ischemia,
522
Patel and Ohman
JACC VOL. 66, NO. 5, 2015
AUGUST 4, 2015:521–3
Should the Guidelines Be Revisited?
revascularization, and myocardial infarction. All of
last 2 years of the trial for the selective invasive group
these endpoints were reduced at 5 years and remain
is now substantially lower at 2.67 compared with the
important to patients and clinicians. This may in part
early part of the trial. This suggests that something
be due to the fact that the mortality endpoint from
changed in this cohort in the last 4 years of the
5 to 10 years is evaluated through a national database
10-year follow-up period. However, the routine
and not in the same fashion as during the trial. There
invasive strategy had event rates at 3.49/100 person-
is also no information on revascularization during
years, almost mimicking the event rate in the early
follow-up beyond 5 years. However, through careful
phase of the selective invasive group. Patients who
analysis, they have explored the rate of revas-
had already had their anatomy evaluated may in turn
cularizations up to 5 years and its potential effect on
be managed with less revascularization (10). Although
later mortality. These findings do not provide any
this remains speculation, it speaks to 2 issues:
further insight into why the mortality curves changed
namely, relatively a lack of power to detect important
from 5 to 10 years of follow-up.
mortality rates, but also an understanding that the
A consideration is that the treatment of patients
with coronary artery disease is not static. Cardiologists
follow-up treatment strategies are an important part
of a trial and may affect subsequent outcomes.
sometimes quickly adapt new treatment strategies
So, what can the practicing physicians take from
for perceived improvement in outcomes. One such
these findings? First are the possible explanations for
example is the rapid uptake of drug-eluting stents in
observed long-term mortality in the RITA-3 trial. As
the early 2000s, which led to a quick adoption in a
noted, it is not clear if this loss of mortality reduction
largely off-label population (9). This ongoing change
is due to attenuation of a direct treatment effect,
in practice could also play a role in a cohort of patients
treatment crossovers over the long-term follow-up,
who were managed by a selective invasive approach;
changing clinical therapeutics with improved anti-
because the information became known to the prac-
platelet and antithrombotic therapies, or simply the
ticing community 5 years after the start of the trial,
play of chance. Although each possibility may play a
patients who were readmitted later after the initial
role, it seems most likely that the significant treatment
completion of the trial may have been managed with a
effect from the initial study, the widespread clinical
more invasive approach. However, a more conserva-
presentation of the trial findings, and guideline rec-
tive approach may have been selected for those who
ommendations caused clinical practice to shift toward
were already revascularized in the invasive arm (10).
more routine invasive care. This is what we would
Unfortunately,
hope happens with an active quality cycle in which
the
subsequent
revascularization
strategies beyond the 5-year time point in the RITA-3
findings are incorporated into clinical practice (11).
trial are not known. The authors acknowledge this
These findings of RITA-3 can therefore be inter-
limitation; yet, the data are actually of some interest
preted as an important milestone of understanding
when the mortality curves are examined closely.
the effect of an early invasive strategy on long-
In the report, the authors have calculated the
term outcomes. As such, the trial suggests that the
mortality rates (per 100 person-years) in the 2 treat-
benefit observed initially may not be translated into a
ment groups in 2-year intervals throughout the
longer benefit. How much of this attenuation can be
10-year period. In the first 4 years of the trial, the
ascribed to a change in practice pattern remains un-
investigators do not know the results of the 5-year
clear. However, we should be heartened by the fact
mortality outcomes, but they become known later
that physicians may be using the latest clinical trial
because of the publication showing a significant
data to improve the care for their patients with
reduction in mortality after the initial 5 years of
ACS, and therefore, our ability to interpret late out-
follow-up. In examining the mortality curves, some
comes may be heavily affected by the improving
interesting features emerge. During the first 4 years,
physicians’ performance around guidelines and the
the annual mortality rate is 2.46 for the routine
optimal care for patients with ACS. This is a very
invasive strategy versus 3.38 for the selective inva-
positive message indeed if you are a patient, but it
sive strategy. If one assumes that it took 1 to 2 years to
makes it much harder if you are a researcher or
disseminate the early trial results after the 5-year
guidelines writer in the field of cardiology.
results, then examining the mortality rates at the
tail end of the trial would be important because pa-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
tients who were largely managed selectively inva-
Manesh R. Patel, Duke Clinical Research Institute,
sively may have undergone more invasive treatment
Duke
strategies for their recurrent ACS event. In this re-
Terrace Level, 2400 Pratt Street, Durham, North
gard, the mortality rate per 100 person-years in the
Carolina 27705. E-mail: [email protected].
University
Medical
Center,
Room
0311
Patel and Ohman
JACC VOL. 66, NO. 5, 2015
AUGUST 4, 2015:521–3
Should the Guidelines Be Revisited?
REFERENCES
1. Amsterdam EA, Wenger NK, Brindis RG, et al.
2014 ACC/AHA guideline for the management of
patients with non–ST-elevation acute coronary
syndromes: a report of the American College of
Cardiology/American Heart Association Task Force
on Practice Guidelines. J Am Coll Cardiol 2014;64:
randomized comparison of an early invasive versus
selective invasive management in patients with
non–ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 2010;55:858–64.
2. Hamm CW, Bassand JP, Agewall S. ESC guidelines
5. Fox KA, Poole-Wilson PA, Henderson RA, et al.
Interventional versus conservative treatment
for patients with unstable angina or non-STelevation myocardial infarction: the British Heart
for the management of acute coronary syndromes in
patients presenting without persistent ST-segment
elevation. Eur Heart J 2011;32:2999–3054.
Foundation RITA 3 randomised trial. Randomized
Intervention Trial of unstable Angina. Lancet
2002;360:743–51.
3. Cannon CP, Weintraub WS, Demopoulos LA,
et al., for the TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an
Invasive or Conservative Strategy)—Thrombolysis
In Myocardial Infarction 18 Investigators. Com-
6. FRagmin and Fast Revascularisation during
InStability in Coronary artery disease Investigators. Invasive compared with non-invasive
treatment in unstable coronary-artery disease:
FRISC II prospective randomised multicentre
parison of early invasive and conservative strategies in patients with unstable coronary syndromes
treated with the glycoprotein IIb/IIIa inhibitor
tirofiban. N Engl J Med 2001;344:1879–87.
study. Lancet 1999;354:708–15.
2645–87.
4. Damman P, Hirsh A, Windhausen F, et al., for
the ICTUS Investigators. 5-year clinical outcomes
in the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial: a
7. Henderson RA, Jarvis C, Clayton T, Pocock SJ,
Fox KAA. 10-year mortality outcome of a routine
invasive strategy versus a selective invasive
strategy in non–ST-segment elevation acute coronary syndrome: the British Heart Foundation
RITA-3 Randomized Trial. J Am Coll Cardiol 2015;
66:511–20.
8. Fox KA, Poole-Wilson P, Clayton TC, et al.
5-year outcome of an interventional strategy in
non-ST-elevation acute coronary syndrome: the
British Heart Foundation RITA-3 randomised trial.
Lancet 2005;366:914–20.
9. Kandzari DE, Roe MT, Ohman EM, et al. Frequency, predictors, and outcomes of drug-eluting
stent utilization in patients with high-risk non-STsegment elevation acute coronary syndromes. Am
J Cardiol 2005;96:750–5.
10. Bhatt DL, Roe MT, Peterson ED, et al., for the
CRUSADE Investigators. Utilization of early invasive
management strategies for high-risk patients with
non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality
Improvement Initiative. JAMA 2004;292:2096–104.
11. Califf RM, Peterson ED, Gibbons RJ, et al.
Integrating quality into the cycle of therapeutic
development.
1895–901.
J
Am
Coll
Cardiol
2002;40:
KEY WORDS long-term mortality, NSTEMI,
revascularization, unstable angina
523