Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: A substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials

Article (PDF Available)inEuropean Heart Journal 33(1):51-60 · March 2009with6 Reads
DOI: 10.1093/eurheartj/ehp009 · Source: PubMed
Abstract
The aim of this study was to compare benefits and risks of a routine invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes. We randomly assigned 184 women, either to a routine or to a selective invasive strategy as a substudy to the OASIS 5 trial, who were followed for 2 years. Meta-analysis of data from previous randomized trials was also done. There were no significant differences between the two treatment strategies in the primary outcome death/myocardial infarction (MI)/stroke [21.0 vs. 15.4%, HR = 1.46, 95% CI (0.73-2.94)], in the secondary outcome death/MI [18.8 vs. 14.3%, HR = 1.39, 95% CI (0.67-2.88)], or separately analysed outcomes MI [12.9 vs. 13.3%, HR = 0.95, 95% CI (0.42-2.19)] or stroke [2.3 vs. 4.4%, HR = 0.67, 95% CI (0.12-3.70)]. However, there were significantly more deaths after 1 year (8.8 vs. 1.1%, HR = 9.01, 95% CI (1.11-72.90) and a higher rate of major bleeding at 30 days [8.8 vs. 1.1%, HR = 11.45, 95% CI (1.43-91.96)] in the routine invasive strategy group. A meta-analysis including 2692 women in previous randomized trials, with a gender perspective, showed no significant difference in the composite outcome death/MI, OR = 1.18, 95% CI (0.92-1.53) but a higher mortality with a routine invasive strategy for women, OR = 1.51, 95% CI (1.00-2.29). The rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy compared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined with data from previous trials, there does not appear to be a benefit of an early invasive strategy in women with ACS, which differs from the results in men. These data emphasize the lack of clear evidence in favour of an invasive strategy in women and suggest caution in extrapolating the results from men to women.

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CLINICAL RESEARCH
Interventional cardiology
Early invasive compar ed with a selective invasive
s tra tegy in women with non-ST-elevation acute
coronary s yndr omes: a substudy of the OASIS
5trialandameta-analysisofprevious
r andomized trials
Eva Swahn
1
*
, Joakim Alfredsson
1
, Rizwan Afzal
2
, Andrzej Budaj
3
,
Susan Chrolavicius
2
, Keith Fox
4
, Sanjit Jolly
2
, Shamir R. Mehta
2
,
Robbert de Winter
5
, and Salim Yusuf
2
1
Division of Cardiology, Department of Medical and Health Sciences, Linko¨ping Heart Centre, University Hospital, SE 581 85 Linko¨ ping, Sweden;
2
Department of Medicine,
McMaster University, Hamilton, Canada;
3
Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland;
4
Centre for Cardiovascular Science, University of Edinburgh,
Edinburgh, UK; and
5
Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
Received 7 July 2008; revised 22 December 2008; accepted 5 January 2009; online publish-ahead-of-print 7 February 2009
Aims The aim of this study was to compare benefits and risks of a routine invasive compared with a selective invasive strat-
egy in women with non-ST-elevation acute coronary syndromes.
Methods
and results
We randomly assigned 184 women, either to a routine or to a selective invasive strategy as a substudy to the OASIS 5 trial,
who were followed for 2 years. Meta-analysis of data from previous randomized trials was also done. There were no sig-
nificant differences between the two treatment strategies in the primary outcome death/myocardial infarction (MI)/stroke
[21.0 vs. 15.4%, HR ¼ 1.46, 95% CI (0.732.94)], in the secondary outcome death/MI [18.8 vs. 14.3%, HR ¼ 1.39, 95% CI
(0.672.88)], or separately analysed outcomes MI [12.9 vs. 13.3%, HR ¼ 0.95, 95% CI (0.422.19)] or stroke [2.3 vs. 4.4%,
HR ¼ 0.67, 95% CI (0.123.70)]. However, there were significantly more deaths after 1 year (8.8 vs. 1.1%, HR ¼ 9.01, 95%
CI (1.1172.90) and a higher rate of major bleeding at 30 days [8.8 vs. 1.1%, HR ¼ 11.45, 95% CI (1.43 91.96)] in the
routine invasive strategy group. A meta-analysis including 2692 women in previous randomized trials, with a gender per-
spective, showed no significant difference in the composite outcome death/MI, OR ¼ 1.18, 95% CI (0.921.53) but a
higher mortality with a routine invasive strategy for women, OR ¼ 1.51, 95% CI (1.002.29).
Conclusion The rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy com-
pared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined
with data from previous trials, there does not appear to be a benefit of an early invasive strategy in women with ACS,
which differs from the results in men. These data emphasize the lack of clear evidence in favour of an invasive strategy
in women and suggest caution in extrapolating the results from men to women.
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Keywords Women Non-ST-elevation acute coronary syndrome Invasive strategy
Introduction
Some, but not all, randomized trials have reported a reduction
in myocardial infarction (MI), with a neutral effect on mortality,
with a routine early coronary angiography followed by appropriate
revascularization, compared with a more selective invasive
strategy. There is controversy whether benefits of a routine
invasive strategy in women differ from that in men.
* Corresponding author. Tel: þ46 13 222000, Fax: þ46 13 222171, Email: eva.swahn@lio.se
Published on behalf of the European Society of Cardiology. All rights reserved.
& The Author 2009. For permissions please email: journals.permissions@oup.com.
European Heart Journal (2012) 33,5160
doi:10.1093/eurheartj/ehp009
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The FRISC II trial (Fragmin and Revascularization during
Instability in Coronary artery disease)
1
and the RITA 3 trial (third Ran-
domized Intervention Trial of Unstable Angina)
2
reported a benefit of
early intervention for death or MI in men but not in women,
whereas the TACTICS TIMI-18 trial (Treat angina with Aggrastat
and determine Cost of Therapy with an Invasive or Conservative
Strategy—Thrombolysis In Myocardial Infarction 18), which was
also analysed to look at marker positivity in relation to benefit of an
invasive strategy, indicated a beneficial effect of early intervention
for death or MI in both men and women, at least in patients with elev-
ated markers.
3
Recently, the ICTUS trial (Invasive vs. Conservative
Treatment in Unstable Coronary Syndromes) reported no benefit
with an early invasive strategy in reducing death, MI, or rehospitaliza-
tion for angina symptoms, with similar results in both genders.
4
The aim of this study in women was to determine if an early
invasive strategy with routine coronary angiography (and if appro-
priate, coronary revascularization within 7 days) was superior to
a selective invasive strategy (with coronary angiography only if
symptoms or signs of severe ischaemia occurred) in preventing
death, MI, or stroke at 2 years.
Methods
The current study was a randomized, prospectively designed substudy
of the OASIS 5 trial (Organization to Assess Strategies in Acute
Ischemic Syndromes Investigators). OASIS 5 was an international,
multi-centre, randomized, double blind trial in which fondaparinux
was compared with enoxaparin in patients with unstable angina
pectoris or MI without ST-elevation (NSTEMI). Study design
5
and
results
6
of the OASIS 5 main study are presented in detail elsewhere.
Local ethics committees approved the study protocol. All patients
provided written informed consent.
Study patients
In the OASIS 5 trial, patients were randomly assigned to receive
fondaparinux or enoxaparin within 24 h after onset of symptoms.
Inclusion and exclusion criteria for the substudy were identical to
those of the OASIS 5 main study. Patients were eligible if they met
at least two of the following three criteria: an age of at least 60
years, an elevated level of troponin or creatinine kinase MB isoenzyme
above upper limit of normal (ULN), or electrocardiographic changes
indicative of ischaemia (defined as ST depression at least 1 mm in
two contiguous leads or T-wave inversion . 3 mm or any dynamic
ST shift or transient ST elevation). Patients with contraindications to
low-molecular-weight heparin, recent haemorrhagic stroke, indications
for anticoagulation other than an acute coronary syndrome, age ,21,
pregnancy, co-morbid condition with life expectancy ,6 months, or
severe renal insufficiency (defined as a serum creatinine level of at
least 265 mmol per litre) were excluded.
At the same time as randomization to fondaparinux or enoxaparin;
female patients participating in this substudy (from select centres)
were randomized to a routine coronary angiography (within 4 days
of admission and, if appropriate, revascularization within 7 days of
admission) or to a selective invasive strategy with coronary angiogra-
phy only if they experienced symptoms or signs of severe ischaemia.
Indications for coronary angiography in the selective invasive arm
were: (i) refractory ischaemia, defined as recurrent chest pain/
ischaemic symptoms (with documented characteristic ECG changes:
horizontal ST depression .1 mm indicative of ischaemia) lasting
.5 min, while on ‘optimal’ medical therapy [defined as at least two
anti-anginal treatments (nitrate, b-blocker, calcium antagonist)]; (ii)
new ST-elevation in two contiguous leads, without Q-waves or
T-wave inversion (over 3 mm); (iii) development of haemodynamic
instability, or severe heart failure (Killip class IV); (iv) intractable life-
threatening arrhythmia; (v) incapacitating angina or severe ischaemia
at a stress test before discharge or later during follow-up; (vi)
re-infarction during follow-up. In both study groups, the mode of
revascularization, percutaneous coronary intervention (PCI) or
coronary artery by-pass grafting (CABG), was left to the discretion
of the attending physicians and was based on patient characteristics
and preferences, extent of disease, co-morbidity, and left ventricular
function. If PCI was performed, the use of stents was strongly encour-
aged. At the start of the PCI, patients in the enoxaparin group received
no additional anticoagulant if they had received their subcutaneous
enoxaparin injection 6 h or less before PCI; if the interval was .6h,
the dose of weight-adjusted unfractionated heparin (UFH) was
65 IU/kg intravenously if a glycoprotein (GP) IIb/IIIa antagonist was
used, and 100 IU/kg intravenously if no GP IIb/IIIa antagonist was
used. Doses of heparin were chosen based on recommendations
from the sixth ACCP Consensus Conference on Antithrombotic
Treatment.
7
Patients undergoing PCI within 6 h of the last subcu-
taneous dose of fondaparinux, in the absence of a GP IIb/IIa antagonist,
received an additional 2.5 mg intravenous fondaparinux. If the PCI was
done 6 h or more after the last subcutaneous dose of fondaparinux,
2.5 mg of intravenous fondaparinux (with a GP IIb/IIIa antagonist) or
5.0 mg of intravenous fondaparinux (without a GP IIb/IIIa antagonist)
was administered.
Prior to PCI, all patients should be pre-treated with aspirin and
clopidogrel. Aspirin dose was left to the discretion of the investigator,
but doses ,100 mg was recommended. It was also strongly recom-
mended that if the patient was not previously on clopidogrel, then a
300 mg loading dose should be given prior to catheterization. If the
patient was already on clopidogrel, no loading dose was required prior
to catheterization, but if PCI was performed at the same sitting, a
loading dose of 300 mg should be given before the procedure. Treat-
ment with intravenous GP IIb/IIIa was encouraged in association with PCI.
Outcomes
The primary outcome was the composite of death, MI, or stroke at 2
years. Secondary outcomes included: (i) each of death, MI, and stroke
evaluated separately; (ii) composites of death, MI and death, MI, stroke,
or refractory ischaemia (i.e. ischaemia-driven revascularization).
A central committee of clinicians blinded to the allocated manage-
ment strategy adjudicated death classified by cause, MI, refractory
ischaemia, stroke, and major bleedings.
Either one of the following two criteria was required to meet
the diagnosis of MI: (i) typical rise and fall of biochemical markers of
myocardial necrosis (including troponin, CK-MB, CK) to greater than
two times ULN (three times ULN if within 48 h of PCI; 5 ULN if
within 48 h of CABG; if markers were already elevated, .50% of
the lowest recovery enzyme level from the index infarction) with at
least one of the following: (a) ischaemic symptoms, (b) development
of pathological Q-waves on the ECG, (c) ECG changes indicative of
ischaemia (ST-segment elevation or depression), (d) coronary artery
intervention; (ii) findings of an acute MI at autopsy.
Major bleeding was defined as clinically overt bleeding with at
least one of the following criteria: fatal, symptomatic intracranial
haemorrhage, intraocular haemorrhage leading to significant vision
loss or decrease in haemoglobin (Hb) of 30 g/L, (with each blood
transfusion unit counting for 10 g/L) or requiring transfusion of
2 U of blood.
E. Swahn et al.52
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Refractory ischaemia was defined as recurrent chest pain or
ischaemic symptoms lasting . 5 min with characteristic ECG changes
indicative of ischaemia while on optimal medical therapy (at least
two anti-anginal treatments) and leading to additional intervention
(such as thrombolytic therapy, cardiac catheterization, or insertion
of intra-aortic balloon pump) within 48 h of onset of the episode.
Meta-analysis
A computerized literature search was conducted from 1950 through
November 2008 of the MEDLINE database using the search terms
invasive strategy, conservative strategy, selective invasive strategy,
acute coronary syndromes, NSTE MI, non-Q-wave MI, and unstable
angina. We restricted the search to controlled clinical trial or
meta-analysis. We also contacted experts in the field and performed
hand searching through cross-references.
An invasive strategy was defined as the referral of all patients with
non-ST-elevation acute coronary syndrome (NSTE ACS) for coronary
angiography, followed by revascularization if suitable. A selective inva-
sive strategy was defined as a strategy with initial pharmacological
treatment followed by coronary angiography (and subsequent revascu-
larization if suitable) only in patients with symptoms of ischaemia or
severe signs of ischaemia on non-invasive stress testing.
Trials were considered for inclusion if they enrolled patients with
NSTE ACS (NSTEMI or unstable angina) and randomly allocated
patients to receive a routine invasive strategy or a selective invasive
strategy. Trials were excluded if the majority of patients enrolled
had stable angina or ST-elevation MI. Trials were not considered
for inclusion if fibrinolytic therapy was administered to all patients,
if coronary angiography was required before randomization, or if
randomization process was inadequate.
Finally, we initially excluded all trials without published sex-specific
outcome data (death and MI). In addition, we obtained information
(by personal communication with the principal investigator) on sex-
specific outcome data from the latest trial that fulfilled the criteria
to be considered for inclusion.
Sample size estimate and statistical analysis
Based on the overall results of the FRISC II trial, we assumed a
reduction in the rate of death or MI from 17.5 to 12.5% at 3 years
with a routine invasive strategy. To detect a relative risk reduction
of 28.5%, with 80% power, a sample size of 1600 was planned.
Because of slow inclusion rate in the substudy, only 184 patients
were recruited when the OASIS 5 main trial was stopped. However,
a decision was made to follow, in a blinded fashion, all randomized
patients in the substudy for 2 years.
At the same time as randomization to enoxaparin or fondaparinux,
patients included in the substudy were randomized to routine or selec-
tive invasive strategy. The randomization scheme was stratified by site
using blocks of size 2 and 4. The curtailment in the sample size as well
as follow-up time reduced the effective power substantially to about
12% to detect the hypothesized reduction in outcome (two-sided
a
¼ 0.05), but we continued the study as the data could contribute
usefully to a meta-analysis of the relevant data from previous trials
with a gender perspective.
Means and percentages are used to describe baseline and
other characteristics. Outcomes are presented as hazard ratios with
95% confidence intervals. Furthermore, selected outcomes are sum-
marized by Kaplan Meier curves. No adjustment was made for mul-
tiple testing.
A meta-analysis of randomized trials of routine invasive vs. selective
invasive strategies, with separate data for the genders, was undertaken
using the method described by Yusuf et al.
8
and follows the approach
utilized and extensively described by Mehta et al.
9
This approach uses
an assumption-free model and weights the analyses in proportion to
the information (number of events) contributed from each trial. For
FRISC II, RITA 3 (published results), ICTUS (personal communication
by R.W.) and OASIS 5 women substudy, 1-year outcomes were used
and for TACTICS TIMI-18, the published 180-day outcomes were
used. Data on outcome from each of the published studies were
independently extracted by two investigators. Odds ratios (OR) with
95% confidence interval (CI) for the composite outcome death or
MI and for mortality were reported. Heterogeneity was assessed
with Q-statistic. The level of significance used was 0.05 (two-sided).
Statistical software used for the meta-analysis was Comprehensive
Meta-analysis V 2.0 (Biostat Inc., Englewood, NJ, USA).
Results
A total of 92 patients were randomly assigned to a routine invasive
strategy and 92 patients to a selective invasive strategy. Almost all
patients were recruited from Sweden (108) and Poland (73). Nine
patients were lost to long-term follow-up, but they were equally
distributed between routine invasive (five patients) and selective
invasive (four patients) strategy. Baseline characteristics are
shown in Table 1. Mean age was 68 years in both groups. Almost
80% of the patients had troponin or CKMB above ULN and 86%
had any ECG abnormality. During initial hospitalization, 88 patients
(96%) in the routine invasive arm and 37 patients (40%) in the
selective invasive arm underwent coronary angiography, followed
by revascularization in 53 patients (58%) and 28 patients (30%),
respectively (Table 2). During the whole study period, 89 patients
(97%) in the routine invasive and 60 patients (65%) in the selective
invasive group had an angiography performed. In the routine inva-
sive group, 44 patients (48%) had a PCI performed and 15 patients
(16%) underwent CABG compared with 36 patients (39%) and 11
patients (12%), respectively, in the selective invasive group. The
proportion of patients receiving thienopyridines before or during
PCI was similar in the two arms, but a larger proportion of patients
in the routine invasive arm received GP IIb/IIIa inhibitors and a
larger proportion of patients in the selective invasive arm received
UFH. The median time from randomization to angiography, PCI,
and CABG differed between the two study groups (51 vs. 156 h,
70 vs. 147 h, and 196 vs. 381 h, respectively) (Table 3). Among
patients subjected to PCI, there was a higher success rate (96.2
vs. 87.9%) and use of stents (82.7 vs. 72.7) in the selective invasive
group when compared with the routine invasive group (Table 4).
There was no statistically significant difference in the primary
outcome of death/MI/stroke [21.0% in the routine invasive group
vs. 15.4% in the selective invasive group, HR ¼ 1.46, 95% CI
(0.73 2.94)] (Figure 1) or in any of the secondary composite out-
comes of death /MI or death/MI/refractory ischaemia (Table 5). We
found no significant differences when MI or stroke was evaluated
separately (Table 5). However, at 30 days, there was a trend
towards a higher rate of death with a routine invasive strategy
compared with a selective invasive strategy [4.3 vs. 1.1%, HR ¼
4.47, 95% CI (0.49 40.70)]. At 1 year, there was a statistically
significant difference in mortality, with eight deaths in the routine
invasive arm compared with one death in the selective invasive
arm [8.8 vs. 1.1%, HR ¼ 9.01, 95% CI (1.1172.90)]. The observed
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difference in mortality at 1 year persisted until the end of follow-up
at 2 years, although the statistical significance was borderline
[8.8 vs. 2.2%, HR ¼ 4.65, 95%CI (0.97 22.20)] (Table 5, Figure 2).
By the end of 2 years, there were eight deaths in the routine
invasive arm compared with two deaths in the selective invasive
strategy arm. Three cases of fatal asystole, two cases of sudden
death, one of cardiogenic shock, and two cases of death due to
other vascular causes (one acute intestinal ischaemia and one
brain damage because of earlier ventricular fibrillation) were
reported in the routine invasive strategy arm. In the selective inva-
sive arm, one death was reported to be caused by haemorrhage
and in one case the cause of death was judged to be unknown.
To evaluate whether any of the invasive treatment modalities
was associated with worse outcome, we assessed outcomes
according to treatment with PCI or CABG, regardless of initial allo-
cation. At 2-year follow-up, there were two deaths (7.7%) among
the 26 patients who had a CABG performed, six deaths (7.5%)
among 80 patients subjected to PCI, and only two deaths in the
78 patients not revascularized (2.6%).
The rate of major bleedings was substantially higher in patients
randomized to the routine invasive strategy at 30 days [8.8 vs.
1.1%, HR ¼ 11.45, 95% CI (1.43 91.96)], and the difference
persisted during long-term follow-up at 730 days [10.0 vs. 2.2%,
HR ¼ 6.90, 95% CI (1.48 32.13)] (Table 5). Of the 11 patients
who had experienced a major bleeding by 2-year follow-up,
eight occurred among patients who were subjected to PCI and
two among patients who had a CABG performed. However,
there were only two deaths among these 11 patients.
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Table 1 Baseline characteristics of women entering the study
Routine invasive (n 5 92) Selective invasive (n 5 92)
Age (years) (mean + SD) 68.2 + 9.2 67.8 + 8.8
Heart rate (b.p.m.) (mean + SD) 72.2 + 15.4 73.2 + 14.5
Systolic blood pressure (mmHg) (mean+ SD) 139.4 + 25.7 138.3 + 21.6
Time from onset of pain to randomization [(h, median (interquartile range)] 11 (7 19) 13 (8 19)
Comorbidity and risk factors n (%) n (%)
History of MI 22 (24) 18 (20)
Previous PCI 7 (8) 11 (12)
Previous CABG 5 (5) 3 (3)
Stroke 4 (4) 4 (4)
Hypertension 57 (62) 63 (67)
Diabetes mellitus 19 (21) 27 (29)
Current smoker 9 (10) 24 (26)
Medications at the time of randomization
Aspirin 70 (76) 71 (77)
Clopidogrel or ticlopidine 27 (29) 28 (30)
Unfractionated heparin 4 (4) 2 (2)
Low-molecular-weight heparin 27 (29) 26 (28)
ACE-inhibitor or ARB 44 (48) 45 (50)
b-blocker 62 (67) 61 (66)
Lipid-lowering drug 26 (28) 37 (40)
Calcium channel blocker 11 (12) 14 (15)
Digoxin 22 (7) 10 (4)
Diuretics 22 (24) 25 (27)
Nitrates 55 (60) 57 (62)
Ischaemic symptoms and signs
ST-depression (1 mm) 44 (48) 42 (46)
Any ECG abnormality 79 (86) 79 (86)
Troponin or CKMB elevation 73 (79) 72 (78)
Diagnosis at study entry
Unstable angina 33 (36) 27 (29)
Suspected MI 59 (64) 65 (71)
MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor
blocker; CKMB, creatinine kinase muscle/brain.
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Although a larger proportion of patients randomized to a
routine invasive as compared with the selective invasive strategy
was initially allocated to treatment with fondaparinux (59 vs.
41%) (Table 2), there was no major difference in the primary
composite outcome death/MI/stroke (17 vs. 18%) or secondary
outcomes MI (14 vs. 13%) or death (4 vs. 7%) between patients
randomized to treatment with fondaparinux vs. treatment with
enoxaparin. There was, however, less major bleedings among
patients allocated to fondaparinux compared with enoxaparin
(1 vs.11%).
Three earlier randomized trials have reported outcome in
women and men separately: FRISC II, RITA 3, and TACTICS
TIMI-18. Data from the ICTUS trial were obtained from the
study investigators. We conducted a meta-analysis based on pre-
viously published data from the first three trials, data provided to
us from ICTUS and regarding women, the present trial. Data
from 1-year outcomes were used from FRISC II, RITA 3,
ICTUS, and OASIS 5 women substudy. Since 1-year data were
not available from TACTICS TIMI-18, outcomes from 6-month
follow-up were used. The meta-analysis indicates benefit with a
routine invasive strategy in men but not in women. Odds ratio
for death/MI, for the routine invasive compared with a selective
invasive strategy, showed no significant benefit in women
[OR¼ 1.18, 95% CI (0.921.53)] compared with men [OR ¼
0.78, 95% CI (0.66 0.93)] (Figure 3). For men, the routine inva-
sive strategy was associated with lower mortality [OR 0.70,
95% CI (0.510.96)], whereas the opposite was found in
women [OR 1.51, 95% CI (1.002.29)] (Figure 4). Heterogeneity
testing indicated heterogeneity between men and women for a
routine invasive compared with a selective invasive strategy
regarding both death/MI (Q ¼ 6.63, P ¼ 0.01) and death (Q ¼
6.3, P ¼ 0.012).
Discussion
In this small substudy of women randomized to routine invasive
strategy compared with selective invasive strategy, there was no
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Table 2 Medication, procedures, and complications
during initial hospitalization
Routine invasive
(n 5 92)
Selective
invasive (n 5 92)
Medication
Aspirin 91 (100) 91 (98.9)
Clopidogrel or ticlopedin 79 (85.9) 70 (76.1)
Dual antiplatelet therapy 79 (85.9) 69 (75.0)
Unfractionated heparin
ivþsc
11 (12) 7 (8)
Low-molecular-weight
heparin
22 (23.9) 20 (21.7)
Enoxaparin (by
allocation)
38 (41) 54 (59)
Fondaparinux (by
allocation)
54 (59) 38 (41)
GP IIb/IIIa 11 (12) 7 (7.6)
ACE-inhibitor or ARB 65 (70.7) 74 (80.4)
b-blocker 87 (94.6) 86 (93.5)
Lipid-lowering drug 81 (88) 79 (85.9)
Cardiac procedures
Coronary angiography 88 (95.7) 37 (40.2)
PCI 42 (45.7) 22 (23.9)
CABG 11 (12.0) 6 (6.5)
Complications
Killip class I 1 (1.1) 5 (5.4)
Killip class II 4 (4.3) 12 (13.0)
Killip classes III and IV 2 (2.2) 0
GP, glycoprotein; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor
blocker; PCI, percutaneous coronary intervention; CABG, coronary artery bypass
grafting.
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Table 3 Cardiac procedures, degree of coronary artery
disease, medication, and complications during
percutaneous coronary intervention during long-term
follow-up
Routine
invasive
(n 5 92), n (%)
Selective
invasive
(n 5 92), n (%)
Coronary angiography 89 (97) 60 (65)
Time to angiography [h,
median (interquartile
range)]
51 (26 84) 156 (7 1838)
PCI 44 (48) 34 (39)
Time to PCI [h, median
(interquartile range)]
70 (23 93) 147 (49 1345)
CABG 15 (16) 11 (12)
Time to CABG [h, median
(interquartile range)]
196 (147 931) 381 (225 1844)
Diseased vessels
a
Total numbers of lesions 66 52
none 22 (24.7) 10 (16.7)
1 42 (47.2) 27 (45.0)
2 7 (7.9) 12 (20.0)
3 or more 18 (20.2) 11 (18.3)
Left main 5 (5.6) 8 (13.3)
Medication prior to or during PCI
b
Thienopyridine 36 (81.8) 29 (80.6)
UFH 17 (38.6) 17 (47.2)
GP IIb/IIIa 15 (34.1) 8 (22.2)
Complications during PCI
b
Vascular site complications 3 (6.8) 0
Other
c
4 (9.1) 0
h, hours; SD, standard deviation; PCI, percutaneous coronary intervention; CABG,
coronary artery bypass grafting; UFH, unfractionated heparin; GP, glycoprotein.
a
In patients that were subjected to coronary angiography.
b
In patients that had a PCI performed.
c
One new thrombus during angiography, one catheter thrombus, and two
dissections.
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benefit with routine invasive strategy on any of the outcomes
examined. There was, however, a trend towards a higher rate of
the composite outcome death/MI with the routine invasive strat-
egy, which is in accordance with the findings in women enrolled
in the FRISC II (12.4% with a routine invasive vs. 10.5% with a
selective invasive strategy) and RITA 3 (8.6% with a routine invasive
vs. 5.1% with a selective invasive strategy) trials.
Surprisingly, we found a trend towards a higher mortality rate
and also a significant excess in major bleeds associated with a
routine invasive strategy in women with NSTE ACSs.
Consistent with the overall results of several previous random-
ized trials comparing a routine invasive with a selective invasive
strategy
10 12
and a meta-analysis of previous trials,
9
we observed
a trend to an increased risk in early mortality, but unlike the pre-
vious trials, we did not observe a compensatory late benefit with a
routine invasive strategy.
When these results are put into the perspective of earlier trials
addressing the effect of a routine invasive strategy in women, there
is a trend towards an adverse effect. The 1-year mortality rates in
the routine invasive and the selective invasive arms, respectively,
were 4.0 vs. 3.2% in FRISC II and 5.1 vs. 2.4% in RITA 3, and in
TACTICS TIMI-18, the corresponding 180-day mortality rates
were 3.8 vs. 3.6%.
1 3
These trials are consistent with the
present study and collectively indicate little apparent benefit on
major clinical outcomes with a routine invasive strategy in
................................................................................
................................................................................
................................................................................
................................................................................
Table 5 Outcomes
Routine
invasive
(n 5 92),
n (%)
Selective
invasive
(n 5 92),
n (%)
Hazard ratio
(95% CI)
2 years
Death/MI/
stroke
19 (21.0) 14 (15.4) 1.46 (0.73 2.94)
Death/MI/RI 19 (21.0) 19 (20.8) 0.99 (0.52 1.90)
Death/MI 17 (18.8) 13 (14.3) 1.39 (0.672.88)
Death 8 (8.8) 2 (2.2) 4.65 (0.97 22.20)
MI 11 (12.9) 12 (13.3) 0.95 (0.42 2.19)
Stroke 2 (2.3) 4 (4.4) 0.67 (0.12 3.70)
Major bleeding 9 (10.0) 2 (2.2) 6.90 (1.48 32.13)
30 days
Death/MI/
stroke
9 (9.8) 4 (4.3) 2.18 (0.66 7.17)
Death/MI/RI 11 (12.0) 10 (10.9) 1.02 (0.43 2.43)
Death/MI 8 (8.7) 4 (4.3) 1.97 (0.586.63)
Death 4 (4.3) 1 (1.1) 4.47 (0.49 40.70)
MI 4 (4.4) 3 (3.3) 1.19 (0.26 5.40)
Stroke 1 (1.1) 1 (1.1) 1.02 (0.06 16.93
Major bleeding 8 (8.8) 1 (1.1) 11.45 (1.4391.96)
180 days
Death/MI/
stroke
14 (15.2) 8 (8.7) 1.75 (0.734.20)
Death/MI/RI 15 (16.3) 13 (14.1) 1.08 (0.51 2.30)
Death/MI 13 (14.1) 7 (7.6) 1.84 (0.73 4.65)
Death 7 (7.6) 1 (1.1) 7.47 (0.91 61.52)
MI 7 (7.8) 6 (6.6) 1.08 (0.36 3.25)
Stroke 1 (1.1) 3 (3.3) 0.41 (0.04 3.99)
Major bleeding 8 (8.8) 1 (1.1) 11.45 (1.4391.96)
1 year
Death/MI/
stroke
15 (16) 11 (12) 1.45 (0.663.20)
Death/MI/RI 15 (16.3) 16 (17.4) 0.92 (0.45 1.88)
Death/MI 13 (14.1) 10 (10.9) 1.36 (0.593.13)
Death 8 (8.8) 1 (1.1) 9.01 (1.11 72.90)
MI 7 (7.8) 9 (9.9) 0.78 (0.29 2.14)
Stroke 2 (2.3) 3 (3.3) 0.86 (0.14 5.26)
Major bleeding 9 (10.0) 1 (1.1) 13.35 (1.68 105.9)
MI, myocardial infarction; RI, refractory ischaemia.
Figure 1 Cumulative risk of death, myocardial infarction (MI),
or stroke through long-term follow-up. Hazard ratio for death,
myocardial infarction, or stroke at 2 years, 1.46 (95% confidence
interval 0.73 2.94).
................................................................................
................................................................................
Table 4 Percutaneous coronary intervention analysis
by lesion
Routine
invasive
(n 5 66), n (%)
Selective
invasive
(n 5 52), n (%)
Successful PCI
Complete success 58 (87.9) 50 (96.2)
Partial success 2 (3.0) 0
Stent use
BMS 29 (43.9) 31 (59.6)
DES 19 (28.8) 12 (23.1)
No stent 18 (27.3) 9 (17.3)
PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting;
BMS, bare metal stent; DES, drug-eluting stent.
E. Swahn et al.56
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women. In the present study, the difference in 1-year death rates
between routine invasive and selective invasive strategy was
larger; 8.8 and 1.1%, respectively, a concerning trend that strongly
merits further studies.
We were surprised that despite recruiting a relatively small
number of patients, we observed a significant increase in mortality.
The large apparent excess in mortality observed in our trial is likely
to be an exaggeration, perhaps due to chance, but our data are
directionally consistent with the findings of several previous
studies. However, no study had enough power to show a statisti-
cally significant difference separately in outcomes in women.
Gender-specific data from all presently available studies, taken
together in our meta-analysis, indicate that in women there is
little benefit with a routine invasive strategy compared with a
more selective approach. The meta-analysis includes all patients
in the studies and does not account for the possibility of differ-
ences in benefit from a routine invasive strategy within certain sub-
groups, e.g. patients with elevated markers of necrosis. Although
our meta-analysis consists of five trials, it is based on only 2692
patients with few events (97 deaths and 263 death/MI), but the
lower CI limits indicate that, at best, the benefit with a routine
invasive strategy is likely to be small. However, this question is
best resolved by a large prospective randomized trial involving
women. In men, in contrast to what we found in women, our
meta-analysis confirmed a significant benefit for both death and
death/MI with an invasive strategy. Hence, our meta-analysis
indicates heterogeneity between the genders in the effect of a
routine invasive strategy. In a recent meta-analysis by O
´
Donoghue
et al.,
13
where sex-specific data from eight randomized trials had
been extracted, the overall analysis showed a non-significant 11%
higher odds for death with an invasive strategy in women [OR
1.11, 95% CI (0.721.70)] contrasting an also non-significant 11%
Figure 2 Cumulative risk of death through long-term
follow-up. Hazard ratio for death at 2 years, 4.65 (95% confi-
dence interval 0.97 22.20).
Figure 3 Meta-analysis including 1-year outcome in FRISC II, RITA 3, ICTUS, and OASIS 5 women substudy and 180 days outcome in
TACTICS TIMI-18. Odds ratio for the composite outcome death/myocardial infarction was calculated in routine invasive compared with selec-
tive invasive strategy. Heterogeneity in men vs. women P ¼ 0.01.
Early invasive compared with a selective invasive strategy in women with NSTE ACS 57
by guest on December 30, 2015http://eurheartj.oxfordjournals.org/Downloaded from
lower odds for death with an invasive strategy in men [OR 0.89,
95% CI (0.58 1.35)].
The two study groups in the present study were well
matched regarding age, myocardial damage marker elevation, and
ST-segment depression. There were more current smokers and
diabetics in the selective invasive group; otherwise there were
no major differences between the groups regarding risk factors
and medical history that could explain the large difference in
outcome. In our study, the effect of intervention is identical with
or without elevated troponin when compared with TACTICS
TIMI-18.
3
The interaction P-value is 0.508.
The use of evidence-based medications in this study was high,
and there were no major differences between the two treatment
arms. In the routine invasive strategy and selective invasive arm,
respectively, almost all patients received aspirin (100 vs. 99%)
and a large proportion was given clopidogrel/ticlopidine (86 vs.
76%), ACE-inhibitor (ACE-I)/angiotensin receptor antagonist
(ARB) (71 vs. 80%), b-blocker (95 vs. 94%), and lipid-lowering
drug (88 vs. 86%). For comparison, in TACTICS TIMI-18 (where
discharge medication is reported), use of aspirin was similarly
high (98%), but the use of ACE-I/ARB (18%), b-blocker (61%),
and statins (45%) was substantially lower. In TACTICS TIMI-18,
GpIIb/IIIa inhibitors were routinely used prior to the angioplasty
as compared with 23.8% in our study. However, a meta-analysis
of all trials of GP IIb/IIIa inhibitors in ACS has failed to demonstrate
any benefit in women.
14
The proportion of patients receiving thie-
nopyridines was not reported in earlier trials, but it is likely to have
been lower than in the current trial. Could the higher use of effec-
tive medications in the present study, compared with previous
trials, explain the very low mortality rate in the selective invasive
strategy arm? With an optimal medical therapy, there may be
little to gain from a routine invasive strategy. In contrast, restricting
the use of invasive procedures to patients who are not stabilized
on optimal medical therapy may select those who benefit most
from, while at the same time minimizing hazards associated with,
such procedures. This may be more important in women who
have less severe coronary artery disease. As expected, among
patients that had an angiography performed, patients in the
routine invasive arm had less severe coronary artery disease.
Also as expected, by design, there was an important difference
between the study groups in time from randomization to invasive
procedures, with longer time delays in the selective invasive group.
Whether early invasive procedures are associated with lower pro-
cedural success rates and higher complication rates as suggested by
our data can only be resolved by a large trial that randomizes
patients to early vs. more delayed invasive strategy. As mentioned,
in an earlier meta-analysis, routine invasive strategy was associated
with higher early mortality and MI (early hazard), which appeared
to be compensated by a later benefit.
9
The early hazard as well as
lack of later benefit may be more pronounced in women who tend
to be older and experience higher risk of procedural complications
with an invasive strategy. Combined with less significant coronary
artery disease, women may have less to gain and more risks with
invasive procedures.
Patients in the routine invasive group were more often allocated
to fondaparinux (59 vs. 41%), but fondaparinux was not associated
with worse outcome as there were two deaths in patients treated
with fondaparinux (4.3%) and six deaths in patients allocated to
enoxaparin treatment (6.5%). Adjustment for this imbalance did
not alter the results.
Figure 4 Meta-analysis including 1-year outcome in FRISC II, RITA 3, ICTUS, and OASIS 5 women substudy and 180 days outcome in
TACTICS TIMI-18. Odds ratio for death was calculated in routine invasive compared with selective invasive strategy. Heterogeneity in men
vs. women P ¼ 0.012.
E. Swahn et al.58
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In the FRISC II trial, the mortality rate among women randomized
to early invasive strategy and treated with CABG was 9.9% com-
pared with 1.2% among men, whereas the corresponding numbers
for patients treated with PCI were 1.5 and 1.0%. The higher risk
associated with CABG was suggested as an explanation for lack of
benefit with an invasive strategy among women in the FRISC II
trial. We assessed mortality according to actual mode of revas-
cularization. There were two deaths among CABG-treated patients
(7.7%) and six deaths among PCI-treated patients (7.5%). Hence,
CABG-related mortality in our study does not appear to be a
major reason for the higher mortality with an invasive strategy in
this study. Indeed the lowest mortality rate (2.6%) was observed
in those who did not undergo any revascularization procedure.
Another important finding in this study was the high rate of
major bleedings associated with the routine invasive strategy.
A marked difference in bleeding rates was evident early during
the study (at 30 days: 8.8 vs. 1.1%, P ¼ 0.004), with few further
additional events later on in either group. Accordingly, increased
risk of major bleeding was consistent and statistically significant
at all time points during the study. There were 11 major bleedings
in the current study, and 8 of these occurred in patients subjected
to PCI, 2 in patients who had a CABG performed, and only 1 in
patients not revascularized. These higher rates of bleeding with
an invasive strategy have been reported in earlier studies compar-
ing invasive and conservative strategies in NSTE ACS.
4,10 12
Women also are at higher risk for bleeding complications. For
example, in the TACTICS TIMI-18 trial, the rate of major bleeding
in women undergoing PCI was 8.3% compared with 2.9% in men.
3
Increased bleeding rates have been reported in ACS treated
with GP IIb/IIIa inhibitors, especially in combination with thieno-
pyridines
15
and among women.
16
Although the numbers are too
small to draw any firm conclusions, we found a three times
higher mortality among patients experiencing a major bleeding;
there were two deaths among the 11 patients (18%) that experi-
enced a major bleeding and 8 deaths among the 173 patients
(6%) that did not experience a major bleeding. However, several
recent studies have highlighted that bleeding in patients with
ACS increases both short-term and long-term risk of death.
17 19
The high bleeding rate among women treated invasively is
worrying and needs further studies.
Limitations
The small sample size and the shortened follow-up are important
limitations. The results should therefore be interpreted with great
caution and in the context of similar data from other trials. Hence,
our meta-analysis is more reliable than an emphasis on the results
of any specific trial in isolation.
Conclusions
Women with NSTE ACS did not seem to benefit from a routine
invasive strategy, but instead experienced higher mortality and
bleeding. The results taken together with previous trials indicate
a lack of benefit with a routine invasive strategy in women. This
suggests that the results from men, with regards to invasive pro-
cedures, may not necessarily apply to women and that large-scale
randomized trials in women are needed to determine the optimal
treatment strategy.
Acknowledgement
We are indebted to patients and investigators who participated in
the study.
Funding
The study was supported by Sanofi-Aventis, Organon, and
GlaxoSmithKline. The sponsor had no role in the study design; the
collection, analysis, or interpretation of the data; the preparation,
review, or approval of the manuscript. E.S. had full access to all data
in the study and takes responsibility for the integrity of the data and
the accuracy of the data analysis.
Conflict of interest: none declared.
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CARDIOVASCULAR FLASHLIGHTS
.............................................................................................................................................................................
doi:10.1093/eurheartj/ehr257
Online publish-ahead-of-print 30 July 2011
Aortic pseudo-aneurysm caused by complete dehiscence
of the left coronary artery 7 years after a composite mechanical-valved
conduit aortic root replacement (Bentall operation)
Pierre Monney*, Cyril Pellaton, Salah Dine Qanadli, and Xavier Jeanrenaud
Service de Cardiologie, Centre Hospitalier Universitaire Vaudois-CHUV, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
* Corresponding author. Tel: þ41 213140010, Fax: þ41 213140055, Email: pierre.monney@chuv.ch
A 65-year-old man was admitted with rapidly
progressive dyspnoea. He had been operated
on for a type A aortic dissection 11 years
earlier (supracommissural replacement), and 4
years later underwent a Bentall operation for
dehiscence of the proximal graft anastomosis
and severe aortic regurgitation.
On admission, high jugular venous pressure
and pulmonary oedema were noted. Acute res-
piratory distress with cyanosis developed in the
supine position and the patient was intubated.
Dynamic electrocardiographic changes with
ST-elevation (IaVL) and ST-depression (V4
V6) occurred when the patient was moved
from the supine (Panel A) to the left lateral pos-
ition (Panel B). A three-dimensional transoeso-
phageal echocardiogram demonstrated a 9
8 cm large aortic pseudo-aneurysm (*), pos-
terior to the composite graft (#), compressing
the left atrium (§), and communicating with
the left ventricular outflow tract through a
large fistula (arrow) with bidirectional flow
(Panels C and E). There was a 5 9mm
orifice (arrowhead) on the left side of the
aortic graft communicating to the
pseudo-aneurysm with dense continuous flow, suggesting dehiscence of the left coronary artery (Panels D and F ). A computed tomo-
graphic scan (Panels G I ) showed the proximal end of the left coronary artery (red arrow) originating from the pseudo-aneurysm,
10 mm apart from the composite graft. Emergency surgery was performed and intraoperative findings confirmed the dehiscence of
the left coronary artery with the main stem floating freely in the pseudo-aneurysmal cavity. Inflammatory markers and blood cultures
were negative.
Complete coronary artery dehiscence is an exceptional cause of pseudo-aneurysm after a Bentall operation; it resulted in extensive
myocardial ischaemia, the myocardial perfusion being exclusively dependent on intra-aneurysmal pressure.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com.
E. Swahn et al.60
by guest on December 30, 2015http://eurheartj.oxfordjournals.org/Downloaded from
    • "We identified 32 relevant clinical trials (Fig. 1). Of these 32 trials [11,16,17,, 12 studies were excluded for being noncontemporary404142434445464748495051 (i.e., low use of dual oral antiplatelet therapy and stenting, or use of fibrinolytic agents), 8 studies were excluded because they had compared an early to a delayed invasive strategy52535455565758 or early systematic angiography and revascularisation versus early elective strategy [59] (angiography and selective revascularisation), 1 was excluded because it had randomized only 88 patients [60], 1 was excluded being a subanalysis on female patients [61] and 1 trial was excluded because it was a randomized comparison of coronary-artery bypass surgery and medical therapy [62] the inclusion criteria and were included in the analysis.Figure 1 shows the flow diagram with information about the selected, included, and excluded clinical studies. "
    [Show abstract] [Hide abstract] ABSTRACT: The Italian Elderly ACS study was the first randomized controlled trial comparing an early aggressive with an initially conservative strategy in patients with non-ST-segment elevation acute coronary syndromes aged ≥75 years, with the results showing no significant benefit of early aggressive therapy. The aim of this study was to evaluate the outcomes of trial patients, according to the treatment actually received during hospitalization. The trial enrolled 313 patients. The primary end point was the composite of death, myocardial infarction (MI), disabling stroke, and repeat hospital stay for cardiovascular causes or bleeding within 1 year. All patients in whom coronary angiography was performed during initial hospitalization were defined as having undergone invasive treatment (182 patients), whereas all patients who did not undergo coronary angiography were classified as medically managed (conservative treatment [CT] group, 131 patients). The primary end point occurred in 53 patients (40.5%) in the CT group and 45 patients (24.7%) in the invasive treatment group (hazard ratio 0.56, 95% confidence interval 0.37 to 0.83, p = 0.003). The invasive treatment group showed significantly lower rates of MI (6% vs 13% in the CT group; hazard ratio 0.43, 95% confidence interval 0.20 to 0.92, p = 0.034) and the aggregate of death and MI (14.3% vs 27.5% CT group; hazard ratio 0.48, 95% confidence interval 0.29 to 0.81, p = 0.004). In conclusion, elderly patients with non-ST-segment elevation acute coronary syndromes treated invasively experienced significantly better survival free from the composite of all-cause mortality, nonfatal MI, disabling stroke, and repeat hospitalization for cardiovascular causes or bleeding. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Dec 2014
  • Article · · The American Journal of Cardiology
  • [Show abstract] [Hide abstract] ABSTRACT: For support of field medical units, the U.S. army is developing a self-contained waste water treatment system to produce portable water for use within the unit. To aid in developing the control strategy and the fault detection/fault isolation logic, a dynamic model of the system is being developed. The first phase of the effort is to develop models of the system's components, such a ultrafiltration, reverse osmosis, ozonation, etc. These models are then combined to obtain a model for the complete system. To the greatest extent possible, fundamental equations form the basis of the models. In determining coefficients for the models, the the data was obtained from the experiments that formed the basis of the design of a pilot plant version of the unit. To refine the model, this data is then supplemented by operational data from the pilot plant.
    Conference Paper · Dec 1977 · The American Journal of Cardiology
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