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SYNERGY Trial Investigators. Enoxaparin vs Unfractionated Heparin in High-Risk Patients With Non–ST-Segment
Elevation Acute Coronary Syndromes Managed With an Intended Early Invasive
Strategy: Primary Results of the SYNERGY Randomized Trial. JAMA. 2004;292(1):45–54. doi:10.1001/jama.292.1.45
Authors are members of the Executive and Steering committees of the SYNERGY Trial.
Context Enoxaparin has demonstrated advantages over unfractionated heparin in
low- to moderate-risk patients with non–ST-segment elevation acute coronary
syndromes (ACS) treated with a conservative strategy.
Objectives To compare the outcomes of patients treated with enoxaparin vs unfractionated
heparin and to define the role of enoxaparin in patients with non–ST-segment
elevation ACS at high risk for ischemic cardiac complications managed with
an early invasive approach.
Design, Setting, and Participants The Superior Yield of the New Strategy of Enoxaparin, Revascularization
and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized,
open-label, multicenter, international trial conducted between August 2001
and December 2003. A total of 10 027 high-risk patients with non–ST-segment
elevation ACS to be treated with an intended early invasive strategy were
Interventions Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin
(n = 4985) was to be administered immediately after enrollment and continued
until the patient required no further anticoagulation, as judged by the treating
Main Outcome Measures The primary efficacy outcome was the composite clinical end point of
all-cause death or nonfatal myocardial infarction during the first 30 days
after randomization. The primary safety outcome was major bleeding or stroke.
Results The primary end point occurred in 14.0% (696/4993) of patients assigned
to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated
heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06).
No differences in ischemic events during percutaneous coronary intervention
(PCI) were observed between enoxaparin and unfractionated heparin groups,
respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs
40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]),
unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary
artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding
was observed with enoxaparin, with a statistically significant increase in
TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P = .008) but nonsignificant excess in GUSTO (Global Utilization
of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs
2.2%, P = .08) and transfusions (17.0% vs 16.0%, P = .16).
Conclusions Enoxaparin was not superior to unfractionated heparin but was noninferior
for the treatment of high-risk patients with non–ST-segment elevation
ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin
and the advantages of convenience should be balanced with the modest excess
of major bleeding.
Medical therapies for non–ST-segment elevation acute coronary
syndromes (ACS) have evolved dramatically over the last decade.1,2 At
the same time, trials in high-risk patients have confirmed the benefit of
an early invasive treatment strategy with diagnostic angiography and subsequent
revascularization, compared with a conservative approach.3,4
Despite the demonstrated superiority of enoxaparin, a low-molecular-weight
heparin (LMWH), compared with unfractionated heparin in clinical trials of
patients with non–ST-segment elevation ACS receiving medical therapy
as their primary treatment strategy, the value of enoxaparin as the principal
antithrombin regimen for ACS continues to be debated.5-12 In
part, the fact that enoxaparin is not more broadly used in this patient population
may be due to insufficient information about its efficacy and safety when
combined with potent antiplatelet therapies in the setting of an early invasive
strategy, including a high rate of percutaneous coronary intervention (PCI).
To define the role of enoxaparin in patients with non–ST-segment
elevation ACS at high risk for ischemic cardiac complications managed with
an early aggressive approach, the Superior Yield of the New Strategy of Enoxaparin,
Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was
SYNERGY was a prospective, randomized, open-label, multicenter, international
trial. The rationale and study design of the trial have been previously published.13 The randomization scheme was by site with a random
block size for each site. SYNERGY was designed to evaluate the efficacy and
safety of enoxaparin vs unfractionated heparin when administered with established
guidelines-based therapy, including glycoprotein (Gp) IIb/IIIa inhibitors,
aspirin, and clopidogrel in high-risk patients who presented with non–ST-segment
elevation ACS and were to be managed with an intended early invasive treatment
Eligible patients had ischemic symptoms lasting at least 10 minutes
occurring within 24 hours before enrollment and at least 2 of the following:
age 60 years or older, troponin or creatine kinase elevation above the upper
limit of normal, or ST-segment changes on electrocardiogram (ECG).13 Patients were to be excluded if they had known or
suspected pregnancy, contraindications to unfractionated heparin or LMWH,
recent (<48 hours) or planned spinal or epidural anesthesia or puncture,
PCI or thrombolytic therapy within the preceding 24 hours, increased risk
for bleeding complications due to recent stroke or surgery, elevated international
normalized ratio (>1.5), past or present bleeding disorder, or creatinine
clearance less than 30 mL/min. All patients provided written informed consent.
The protocol was approved by the institutional review board or ethics committee
at each participating center.
Clinical events, procedures, adverse events, and concomitant medications
were documented during the baseline hospitalization and for patients with
rehospitalization during the first 30 days after enrollment. All patients
were to be contacted 180 days after enrollment for collection of data about
key cardiac events and at 1 year to determine survival status.
The primary efficacy outcome was the composite clinical end point of
all-cause death or nonfatal myocardial infarction (MI) during the first 30
days after randomization. Key secondary outcome measures included the incidence
of death or nonfatal MI at 14 days; the combined incidence of all-cause mortality,
nonfatal MI, stroke, or recurrent ischemia requiring revascularization; and
individual components of this composite at 14 and 30 days after enrollment.
The primary safety end point was the incidence of major bleeding or stroke.
All suspected incidents of MI and stroke were adjudicated by a clinical events
committee that was blinded to treatment assignment.
Enoxaparin or unfractionated heparin was given immediately after enrollment
according to the patient's randomly assigned treatment. Treatment continued
until the patient required no further anticoagulation per the treating physician
and at least through angiography and revascularization, if performed. Intravenous
unfractionated heparin was given according to a weight-adjusted nomogram (bolus
of 60 U/kg [maximum of 5000 U] and initial infusion of 12 U/kg per hour [maximum
of 1000 U/h initially]) with a goal activated partial thromboplastin time
of 1.5 to 2.0 times the institutional upper limit of normal or 50 to 70 seconds.1 Enoxaparin was given subcutaneously at a dose of 1
mg/kg every 12 hours.
Patients could be enrolled even if they had already received LMWH or
unfractionated heparin by the treating physician before randomization; the
randomized assignment was independent of any prior antithrombin treatment.
Detailed recommendations for dosing of enoxaparin and unfractionated heparin
in patients with prior antithrombin treatment, as well as for all patients
during PCI, for sheath removal, and prior to coronary artery bypass graft
(CABG) surgery were provided to all investigators and coordinators.
For patients randomly assigned to receive enoxaparin, catheterization
could be performed anytime after dosing and the sheath removed at least 6
to 8 hours after the last enoxaparin dose. During PCI, if the last enoxaparin
dose was given less than 8 hours before balloon inflation, no additional enoxaparin
was to be given. If the last enoxaparin dose was given 8 or more hours before
balloon inflation, 0.3 mg/kg of enoxaparin was to be given intravenously before
proceeding with PCI. If no intravenous enoxaparin was used during PCI, the
sheath could be removed at least 6 to 8 hours after the last enoxaparin dose,
and if it was used, the sheath could be removed at least 4 to 6 hours after
the intravenous enoxaparin dose. Percutaneous closure devices could be used
based on institutional standard practice.
For patients assigned to receive unfractionated heparin, catheterization
was performed while the patient was receiving unfractionated heparin, and
the sheath could be removed when the activated clotting time (ACT) was less
than 150 to 180 seconds. During PCI the unfractionated heparin infusion was
stopped. Additional intravenous unfractionated heparin was given to achieve
an ACT of 250 seconds (lower if Gp IIb/IIIa inhibitors were used) or an ACT
based on the individual site standards.
For elective bypass surgery procedures, enoxaparin was to be discontinued
at least 8 hours and unfractionated heparin at least 6 hours before surgery.
For emergency procedures, enoxaparin or unfractionated heparin was stopped
and the patients were taken to surgery regardless of the timing of the last
All patients received aspirin at enrollment and daily thereafter at
a dose of 162 to 325 mg. Patients with an allergy or contraindication to aspirin
received clopidogrel (75 mg) at enrollment, and then 75 mg/d. Other agents
were recommended per published guidelines, which were emphasized during site
training.1,2 Glycoprotein IIb/IIIa
inhibitor use was encouraged but not mandated. All other medications were
administered at the physician's discretion.
The study was monitored by an independent data and safety monitoring
board. Prespecified interim analyses and formal stopping rules were established
for both efficacy and futility.
The definitions for MI, bleeding, and stroke used in the trial have
been previously published.13 The definitions
for MI and bleeding also appear in the accompanying systematic overview.14
The original sample size of approximately 8000 patients was based on
an expected 30-day control group event rate of 15%, with 90% power to detect
a clinically meaningful relative reduction of 17% with a 2-sided type I error
rate of 5%. Interim analyses of aggregate event rates were planned with an
option to increase the sample size if anticipated event rates were not observed.
After approximately 4000 patients had been recruited, the sample size was
adjusted to 10 000 patients for 3 reasons. First, the aggregated event
rate was 13.5% (below the anticipated 13.75%), so 217 additional patients
were added. Second, the first 49 patients in one country were all assigned
the same therapy due to a programming error in an automatic randomization
system, and the decision was made to replace those patients in the primary
efficacy analyses although they were followed up for safety assessments. Third,
because the study drug assignment was open label, treating physicians used
nonassigned antithrombin strategies either intentionally or inadvertently.
The impact of postrandomization crossover was estimated; since there was a
potential for dilution of the ability to detect treatment differences due
to these crossover treatment situations, the sample size was increased by
1734 patients. No patients were excluded from the primary analyses because
of postrandomization crossover treatment.
Categorical variables are summarized as percentages and continuous variables
as medians with interquartile ranges. The primary efficacy analysis was the
time to first event in the 2 treatment groups based on an intention-to-treat
strategy (all randomized patients, as randomized) with adjudicated MI results
using the stratified log-rank test. The 49 patients not randomly assigned
were excluded from this analysis.
The SYNERGY protocol prespecified that if enoxaparin was not demonstrated
to be superior to unfractionated heparin, a noninferiority analysis was to
be performed. Using SAS PHREG procedure (version 8.2; SAS Institute Inc, Cary,
NC), a 95% confidence interval (CI) (adjusted for interim analyses; final P = .045) for the hazard ratio for the primary end point
with enoxaparin vs unfractionated heparin was constructed. The upper boundary
for the noninferiority claim was set at <1.1. This boundary was determined
by consensus among the trial steering committee based on an end point of death
or nonfatal MI and extensive data already available on enoxaparin and unfractionated
heparin in similar patient populations. Under the closed-testing procedure
with sequential testing of the superiority and inferiority analyses, the overall
2-sided type I error rate was maintained at 5%.
The primary safety outcomes were major bleeding and stroke. Per-protocol
bleeding was to be assessed by both the TIMI (Thrombolysis in Myocardial Infarction)
and GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries)
criteria during the baseline hospitalization.13 Transfusions
were also collected as part of the safety assessment.
To assess the impact of prerandomization antithrombin therapy and postrandomization
crossovers between enoxaparin and unfractionated heparin after enrollment,
a series of prespecified analyses were performed. Analyses on groups defined
by postrandomization events such as crossovers are recognized to be potentially
biased and exploratory in nature. First, subgroups were constructed based
on prerandomization anticoagulation (none, enoxaparin only, unfractionated
heparin only, or both). Second, an analysis including only patients who received
no prerandomization antithrombin therapy or were randomly assigned to the
same antithrombin that they received before randomization was performed. This
group represents patients without changes in antithrombin therapy before enrollment
or as part of the study drug assignment. Cox proportional hazards modeling
was used to examine whether prerandomization antithrombin treatment had an
impact on the estimate of the treatment effect, and hazard ratios and CIs
were created for each subgroup. Then, an analysis was performed in which all
patients were included in the analysis based on the assigned therapy until
they received the opposite treatment, at which time they were censored. Finally,
a time-dependent covariate model was constructed in which events were attributed
to each drug only during the time it was administered. For each of these models,
the Cox proportional hazards assumption was confirmed and statistical significance
was set at P<.05.
Between August 2001 and December 2003, 10 027 patients were enrolled
from 12 different countries and 467 investigative centers. The primary intention-to-treat
analyses included 4993 patients assigned to receive enoxaparin and 4985 patients
assigned to receive unfractionated heparin (Figure 1). Baseline characteristics were similar between treatment
groups (Table 1). Eligibility
criteria were similar across study drug assignment, with nearly half of patients
enrolled due to age, ECG changes, and elevated biomarkers (Table 2).
In-hospital cardiovascular events and coronary procedures through 30
days are shown in Table 3. Overall,
92% (9188/9978) of patients underwent coronary angiography. Percutaneous revascularization
procedures were performed in 47% (4687/9978) of patients and surgical revascularization
in 19% (1864/9973) of patients. Median time from randomization to angiography
was 22 hours (interquartile range, 6-43 hours). Patients were treated aggressively
with recommended medications including aspirin, clopidogrel, β-blockers,
angiotensin-converting enzyme inhibitors, statins, and Gp IIb/IIIa antagonists
(Table 4). The use of procedures
and concomitant medications was similar in the treatment groups.
The primary end point of death or nonfatal MI by 30 days occurred in
14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of
patients assigned to unfractionated heparin (hazard ratio, 0.96; 95% CI, 0.86-1.06).
Enoxaparin was not superior to unfractionated heparin but fulfilled the noninferiority
criteria (Table 5 and Figure 2).
The primary end point in subgroups defined by prerandomization characteristics
is shown in Figure 3. No differences
in ischemic events reported by the physician during PCI were observed between
enoxaparin and unfractionated heparin, including similar rates of abrupt closure
(31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%]
vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or
emergency CABG surgery (6/2323 [0.3%] vs 8/2363 [0.3%]), respectively.
Bleeding was modestly increased in patients assigned to enoxaparin,
with a statistically nonsignificant excess in GUSTO severe events, although
TIMI major bleeding was significantly higher in patients treated with enoxaparin.
The majority of the absolute bleeding excess resulted from CABG-related events
and no significant differences in transfusion, intracranial hemorrhage, or
thrombocytopenia were observed (Table 6).
In SYNERGY, patients could be enrolled after antithrombin therapy was
already initiated as part of routine care. In total, 75% (7538/9978) of patients
already received unfractionated heparin or LMWH prior to randomization. In
addition, 12% (593/4993) of patients assigned to enoxaparin received unfractionated
heparin and 4% (205/4985) of patients assigned to unfractionated heparin received
enoxaparin after randomization (crossovers). Clinical outcomes and bleeding
by groups defined by prerandomization and postrandomization therapies are
shown in Table 7.
Across a series of comprehensive analyses, when an effort was made to
remove the confounding influence of prerandomization antithrombin therapy
or postrandomization crossovers, enoxaparin appeared to have a relative advantage
with no excess of bleeding. Using censored techniques, enoxaparin was associated
with a reduced hazard for 30-day death or nonfatal MI (0.82; 95% CI, 0.07-0.94)
and a similar TIMI major bleeding hazard (1.06; 95% CI, 0.76-1.49). The time-dependent
covariate analyses showed a trend toward lower hazard of 30-day death or nonfatal
MI (0.93; 95% CI, 0.84-1.03) and TIMI major bleeding (0.95; 95% CI, 0.83-1.09)
The SYNERGY trial enrolled a high-risk patient population treated with
an early invasive treatment strategy. Compared with earlier trials of patients
with non–ST-segment elevation ACS (PURSUIT, PRISM-Plus, GUSTO IV, ESSENCE,
TIMI 11B), patients in SYNERGY were older, managed more aggressively with
routine coronary angiography, PCI, and CABG surgery, and treated with potent
antiplatelet agents.6,8,15-17 In
this setting, treatment with enoxaparin was not superior to but was an effective
alternative to unfractionated heparin. Enoxaparin met the prespecified criteria
for noninferiority with a modest increase in the risk of major bleeding.
Enoxaparin has been extensively evaluated in patients with ACS over
the past 10 years. Efficacy for enoxaparin compared with unfractionated heparin
in the conservative management of patients with non–ST-segment elevation
ACS has been clearly demonstrated with 18% to 20% reductions in death or nonfatal
MI.5-7 In the SYNERGY
population, a less robust beneficial treatment effect of enoxaparin was observed.
Whether this attenuated benefit was because of more aggressive use of other
evidence-based therapies, including Gp IIb/IIIa inhibition, clopidogrel, and
revascularization procedures, or prerandomization antithrombin treatment and
postrandomization crossovers is a complex issue. Importantly, with more than
90% of patients undergoing coronary angiography and 47% undergoing PCI, no
increase in periprocedural ischemic complications was observed, including
thrombus formation, abrupt closure, stroke, or need for urgent CABG surgery.
A systematic overview of more than 20 000 patients with non–ST-segment
elevation ACS from the 6 major trials comparing enoxaparin and unfractionated
heparin has been performed to put SYNERGY in perspective with the totality
of evidence.14 In aggregate, enoxaparin was
associated with a statistically significant reduction in death or nonfatal
MI at 14 days, which was maintained through 30 days (odds ratio, 0.91; 95%
CI, 0.83-0.99). The results are consistent across the 6 trials that included
patients with varying degrees of risk and with evolving concomitant therapies
and treatment strategies.
Overall, patients assigned to enoxaparin had more bleeding. However,
no increase in clinically significant bleeding occurred, including intracranial
hemorrhage, bleeding associated with hemodynamic compromise, or need for transfusions.
Multiple measures of bleeding have been used in clinical trials, including
the GUSTO and TIMI scales and need for transfusions, with continued debate
about the strengths and weaknesses of each assessment tool. Additional investigation
of bleeding risk is needed because complex relationships exist among many
factors including age, renal function, coronary procedures, adjunctive therapies,
and postrandomization crossover therapy. In the systematic overview, no significant
excess was observed of 7-day non-CABG TIMI major bleeding (odds ratio, 1.04;
95% CI, 0.83-1.30) or transfusion (odds ratio, 1.01; 95% CI, 0.89-1.14).14
The impact of the postrandomization crossovers is unknown and it was
not anticipated that 75% of patients would have been started with antithrombin
therapy prior to enrollment in SYNERGY. The increase in sample size midway
through the trial was based on a speculative estimate of this impact. In TIMI
IIB18 only 35% of patients had antithrombin
pretreatment but in the more recent A to Z trial, this practice occurred in
nearly two thirds of patients.19 It appears
that prerandomization antithrombotic therapy and postrandomization crossover
had an important impact on the trial results.
However, interpretation of these findings deserves careful evaluation
because of the complexity of the analyses and the potential for confounding.
The indefinable biases among practitioners about prerandomization treatment
and decisions about postrandomization crossover of antithrombin agent use
in the setting of a trial that was not blinded to the investigators further
complicates the interpretation. In patients without prerandomization antithrombin
therapy, enoxaparin was associated with a 16% relative risk reduction in death
and nonfatal MI at 30 days that is consistent with reductions seen in prior
trials. In patients without prerandomization antithrombin therapy or in whom
prerandomization antithrombin therapy was the same as the randomly assigned
therapy, enoxaparin resulted in a statistically significant 18% relative reduction
in death or nonfatal MI. Bleeding outcomes in these 2 groups of patients were
not increased, and censored analyses and time-dependent covariate analyses
confirmed both the efficacy and lack of increased clinically significant bleeding
risk. The clinical benefit seen in SYNERGY patients without antithrombin therapy
prior to randomization was confirmed in the nearly 9000 patients from the
systematic overview,14 which reported a 12%
relative risk reduction in mortality (0.89; 95% CI, 0.70-1.11) and a statistically
significant 18% relative risk reduction in death or nonfatal MI (0.82; 95%
Analyses of the impact of postrandomization crossover are more complicated
because it is an event that occurs after randomization and is further confounded
by the knowledge of the treatment assignment.20 Overall,
it appears that changing antithrombin therapy during the treatment course
is not associated with any treatment benefit and is associated with an increased
risk of bleeding. Still, caution must be used in interpreting these complex
models, since causality and association cannot be definitively delineated.
Potential biases from the open-label trial design include physician
choices of medical therapies or interventions by knowledge of the treatment
assignment and reporting of clinical outcomes. Investigators were encouraged
in the protocol, at investigator meetings, and in trial newsletters to adhere
to the American College of Cardiology/American Heart Association and European
Society of Cardiology guidelines for the management of patients with ACS regardless
of assigned study drug. The similar use of coronary procedures and medical
therapies in both treatment groups supports our conclusion that investigators
were not biased in medical decisions. All analyses were based on a strict
intention-to-treat principle, all-cause mortality was included in the primary
efficacy composite, and a clinical events committee systematically adjudicated
all MI events without knowledge of the treatment assignment.
The results of pragmatic clinical trials have been heralded as the foundation
for changing practice guidelines and clinical care.21 The
design of the SYNERGY trial, with broad inclusion of high-risk patients in
geographically diverse areas and across different clinical practice settings,
along with definitive end points and an active comparator, strengthen the
importance of these results. In high-risk patients with an intended early
invasive treatment strategy, enoxaparin and unfractionated heparin are safe
and effective alternatives as the antithrombin regimen. Enoxaparin has the
advantages of convenience (fixed dosing without need for monitoring or intravenous
infusion) and a trend toward a lower rate of nonfatal MI with a modest excess
of bleeding. As a first-line agent in the absence of changing antithrombin
therapy during treatment, enoxaparin appears to be superior without an increased
bleeding risk. Changing antithrombin agents in the midst of an episode of
ACS may be hazardous, with an increase in bleeding and less clinical benefit.
Clinical investigators developing trials to evaluate new antithrombotic regimens
in ACS should consider carefully the potential impact of prerandomization
therapy and influence of postrandomization crossovers of therapies on trial
conduct and results.
In high-risk patients with ACS treated with an early invasive strategy
with frequent use of antithrombin therapy prior to enrollment and postrandomization
crossovers, enoxaparin is not inferior to unfractionated heparin. Enoxaparin
carries a modest increase in bleeding and is likely superior when started
as initial first-line therapy without changing to alternative agents.
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