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ORIGINAL CONTRIBUTION
JAMA-EXPRESS
Effects of Ranolazine on Recurrent
Cardiovascular Events in Patients With
Non–ST-Elevation Acute Coronary Syndromes
The MERLIN-TIMI 36 Randomized Trial
David A. Morrow, MD, MPH
Benjamin M. Scirica, MD, MPH
Ewa Karwatowska-Prokopczuk, MD
Sabina A. Murphy, MPH
Andrzej Budaj, MD
Sergei Varshavsky, MD
Andrew A. Wolff, MD
Allan Skene, PhD
Carolyn H. McCabe, BS
Eugene Braunwald, MD
For the MERLIN-TIMI 36 Trial
Investigators
N
ON –ST- ELEVATION ACUTE
coronary syndromes (ACS)
is a heterogeneous condition with multiple possible
etiologies that may contribute to an imbalance in myocardial oxygen supply
and demand, resulting in disruption of
cellular homeostasis and depletion
of myocardial cellular energy stores.1
Contemporary acute management
of this syndrome is aimed primarily
at improving myocardial oxygen supply
through the reduction of flowlimiting coronary thrombosis, and revascularization of underlying obstructive atherosclerosis, in conjunction with
interventions to reduce myocardial oxygen demand.2 Chronic treatment is directed at the twin goals of preventing
additional major cardiovascular events,
and reducing recurrent ischemic symp-
For editorial comment see p 1823.
Context Ranolazine is a novel antianginal agent that reduces ischemia in patients with
chronic angina but has not been studied in patients with acute coronary syndromes (ACS).
Objective To determine the efficacy and safety of ranolazine during long-term treatment of patients with non–ST-elevation ACS.
Design, Setting, and Patients A randomized, double-blind, placebo-controlled,
multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who
were treated with ranolazine (initiated intravenously and followed by oral ranolazine
extended-release 1000 mg twice daily, n=3279) or matching placebo (n=3281), and
followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for
Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial
between October 8, 2004, and February 14, 2007.
Main Outcome Measures The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end
of study. The major safety end points were death from any cause and symptomatic
documented arrhythmia.
Results The primary end point occurred in 696 patients (21.8%) in the ranolazine group
and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P=.11). The major secondary end point (cardiovascular
death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P=.50).
Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine
and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P=.87).
Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with
the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P=.03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%)
receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and
placebo (102 [3.1%]) groups (P=.84). No difference in total mortality was observed
with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P=.91).
Conclusions The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect
the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy.
Trial Registration clinicaltrials.gov Identifier: NCT00099788
www.jama.com
JAMA. 2007;297:1775-1783
toms. 3 Despite advances in antithrombotic therapy, coronary revascularization, and other preventive
therapies, the risk of recurrent events
©2007 American Medical Association. All rights reserved.
Author Affiliations are listed at the end of this article.
Corresponding Author: David A. Morrow, MD, MPH,
TIMI Study Group, Department of Medicine, Brigham
and Women’s Hospital, 75 Francis St, Boston, MA
02115 ([email protected]).
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1775
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
diate or high (ⱖ3) TIMI risk score for
unstable angina/non–ST-elevation MI.9
Patients were ineligible if they had any
of the following major exclusion criteria: cardiogenic shock, persistent STsegment elevation, successful revascularization of the culprit stenosis before
randomization, clinically significant hepatic disease, end-stage renal disease requiring dialysis, treatment with agents
known to prolong the QT interval, abnormalities of the electrocardiogram
that would interfere with interpretation of Holter monitoring for ischemia, or a life expectancy of less than 12
months.9 Race and ethnicity were selfreported using categories defined by the
investigators. The protocol was approved by the relevant institutional review boards at all participating centers. Written informed consent was
obtained from all patients.
Figure 1. Patient Flow Diagram
6560 Patients Randomized
3279 Randomized to Receive Ranolazine
3268 Received Allocated
Intervention
11 Did Not Receive Study Drug
3281 Randomized to Receive Placebo
3273 Received Allocated
Intervention
8 Did Not Receive Study Drug
915 Discontinued Study Drug
Prematurely
286 Had Adverse Experience
8 Protocol Violation
2 Did Not Meet Entrance
Criteria
456 Withdrew Consent to
Treatment
65 Nonadherent
98 Other/Missing
736 Discontinued Study Drug
Prematurely
154 Had Adverse Experience
13 Protocol Violation
6 Did Not Meet Entrance
Criteria
407 Withdrew Consent to
Treatment
62 Nonadherent
94 Other/Missing
7 Lost to Follow-up
2 Lost to Follow-up
3279 Included in Primary
Efficacy Analysis
3281 Included in Primary
Efficacy Analysis
3268 Included in Safety Analysis
11 Excluded (Never Received
Study Drug)
3273 Included in Safety Analysis
8 Excluded (Never Received
Study Drug)
in this population remains substantial, in particular among those patients with indicators of higher risk,
such as diabetes mellitus, ST-segment
depression, or a high TIMI risk score.4
Ranolazine is a piperazine derivative that exerts anti-ischemic actions
without a clinically significant effect on
heart rate or blood pressure.5,6 At clinically relevant concentrations, ranolazine is an inhibitor of the slowly inactivating component of the cardiac
sodium current (late INa), which may
reduce the deleterious effects associated with the intracellular sodium and
calcium overload that accompany and
may promote myocardial ischemia.7,8
Ranolazine is available as an antianginal agent for patients with chronic angina but has not been studied in patients with ACS or for secondary
prevention of major cardiovascular
events in patients with established coronary artery disease. Because of an association between ranolazine and prolongation of the QT interval, the safety
of the drug has been questioned. Therefore, there is a need for additional safety
data to guide its use in patients with
coronary artery disease.7 The Meta-
Study Protocol
bolic Efficiency With Ranolazine for
Less Ischemia in Non−ST-Elevation
Acute Coronary Syndromes (MERLIN)TIMI 36 trial was designed to evaluate
the efficacy and safety of ranolazine as
a novel intervention to reduce cardiovascular death, myocardial infarction
(MI), or recurrent ischemia in the shortand long-term in moderate- to highrisk patients with ACS receiving standard therapy.9
METHODS
Patient Population
Between October 8, 2004, and May 24,
2006, 6560 patients (FIGURE 1) underwent randomization at 442 sites in 17
countries (list online at http://www
.jama.com). The details of the study design have been published previously.9
Eligible patients were aged 18 years or
older; had symptoms consistent with
myocardial ischemia at rest, lasting at
least 10 minutes and present within the
previous 48 hours; and had at least 1
of the following indicators of moderate to high risk of death or recurrent
ischemic events: elevated biomarker of
necrosis, ST depression of at least 0.1
mV, diabetes mellitus, or an interme-
1776 JAMA, April 25, 2007—Vol 297, No. 16 (Reprinted)
The protocol specified that patients
were to receive standard treatment for
non–ST-elevation ACS and secondary
prevention. Eligible patients were randomly assigned in a 1:1 ratio to receive either ranolazine or placebo by a
central computerized system using a
permuted-block randomization, with
stratification according to the responsible physician’s intended initial management strategy (early invasive vs conservative), declared at the time of
randomization.
Study medication was to be administered as 200 mg of ranolazine (or
matching placebo) intravenously over
1 hour, followed with an 80-mg/h intravenous infusion, which was reduced to 40 mg/h for patients with an
estimated creatinine clearance of less
than 30 mL/min (⬍0.50 mL/s), and was
continued for 12 to 96 hours. On
completion of the infusion, study medication (ranolazine extended-release or
matching placebo) was to be continued orally at a dose of 1000 mg twice
daily until the end of the study. The protocol specified a reduction in the dose
for patients with new renal insufficiency, and for those patients experiencing specific adverse events that may
©2007 American Medical Association. All rights reserved.
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RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
be treatment related, including persistent prolongation of the QT interval.9
For patients with dose adjustments
made during the intravenous infusion, oral study drug was continued at
a dose of 750 mg twice daily, 500 mg
twice daily, or 375 mg twice daily, based
on the final infusion rate.9 The dose
could undergo an additional adjustment based on persistence or resolution of the reason for a change.
Patients returned for study visits at
14 days, 4 months, and every 4 months
thereafter, until the end of the study.
The final day of follow-up was February 14, 2007. During follow-up visits,
patients were examined, assessed for adverse events and quality of life, and
blood was sampled for local, central
laboratory testing, or both. Patients who
permanently discontinued the study
drug prematurely during the trial were
followed up by telephone contact. A
digital continuous electrocardiographic Holter monitor for ischemia
(Lifecard CF, Delmar Reynolds, Irvine, Calif) was applied to the patient
at the time of randomization and remained in place for 7 days, including
after hospital discharge. Exercise tolerance testing was performed at 8
months, or the final visit if it occurred
first, in patients able to exercise.
The trial was to be continued until
at least 310 deaths and 730 major cardiovascular events had been reported
to the coordinating center, after which
time all patients were requested to return for a final study visit.
End Points
The primary efficacy end point of the
trial was the first occurrence of any element of the composite of cardiovascular death, MI, or recurrent ischemia.
The major secondary end point was the
first occurrence of a major cardiovascular event defined by the composite
of cardiovascular death, MI, or severe
recurrent ischemia.
Myocardial infarction had to be distinct from the index event and was defined by symptoms suggestive of ischemia/infarction in association with either
electrocardiographic, cardiac bio-
marker, or pathological evidence of infarction using criteria adapted from the
definition developed by the American
College of Cardiology.9,10 Recurrent ischemia included any of the following:
(1) recurrent ischemia with electrocardiographic changes, (2) recurrent ischemia leading to hospitalization, (3)
recurrent ischemia prompting revascularization, and (4) worsening of angina/ischemia by at least 1 Canadian
Cardiovascular Society class of angina
that prompted intensification of antianginal therapy.9 Recurrent ischemia
was considered to be severe if any of the
first 3 criteria were satisfied.
Other secondary end points included failure of therapy, defined as
the composite of cardiovascular death,
MI, recurrent ischemia, a positive
Holter for ischemia, hospitalization for
new or worsening heart failure, or an
early positive exercise tolerance test
(evidence for ischemia before completing 12 minutes of a modified
Bruce protocol or equivalent). Quality
of life was assessed as a secondary end
point using the anginal frequency and
physical limitation scales of the Seattle
Angina Questionnaire11 at 4 months of
follow-up. The prespecified efficacy
end point for assessment of the acute
phase through 30 days was the composite of cardiovascular death, MI,
severe recurrent ischemia, or a positive Holter for ischemia.
Safety end points included death from
any cause, the composite of death from
any cause or any cardiovascular hospitalization, the incidence of symptomatic documented arrhythmia, and clinically significant arrhythmias detected
during protocol-related Holter monitoring. Symptomatic documented
arrhythmias included any symptomatic arrhythmia that led to or prolonged hospitalization or was deemed
medically important by the investigator and was documented by any form of
electrocardiographic monitoring.
All elements of the primary composite and major secondary efficacy end
points, as well as hospitalization for new
or worsening heart failure, and symptomatic documented arrhythmia were
©2007 American Medical Association. All rights reserved.
adjudicated by a blinded clinicalevents committee.9
Statistical Analyses
The efficacy analysis was a hierarchical testing of the primary followed by
the secondary hypotheses in a prespecified order using a closed testing procedure. Once a test result was nonsignificant, analyses of the remaining
secondary end points were considered
exploratory. This process was designed to ensure preservation of the intended overall type I error for the entire closed test. The trial was designed
to have a statistical power of at least 90%
to detect a 20% relative risk reduction
with ranolazine with respect to the major secondary end point, assuming an
incidence of 18% at 1 year in the placebo group.
All efficacy analyses were conducted according to the intention-totreat principle. The analysis of the primary end point included all primary
efficacy events known to have occurred after randomization through the
patient’s final study visit. The primary
and major secondary efficacy analyses
were performed by using the log-rank
test stratifying by the intention to use
an early invasive strategy. Hazard ratios (HRs) and 95% confidence interval (CIs) were estimated by using a Cox
proportional hazards regression model
with effects for treatment and intention for early invasive strategy. Event
rates are presented as Kaplan-Meier failure rates at 12 months.
All safety analyses were performed
according to the actual treatment received (a single dose or more) by the
patient. Periodic assessments of safety
were performed by an independent data
and safety monitoring board. One
planned interim analysis of efficacy
based on cardiovascular death was performed by using a Fleming-HarringtonO’Brien12 stopping boundary. The critical 2-sided P value for the primary
efficacy analysis, after correction for interim analysis, was .0497.
Our study was an investigatorinitiated clinical trial by the TIMI Study
Group, designed in conjunction with
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1777
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
the steering committee with review by
the trial sponsor. The investigators had
free and complete access to the data.
Data coordination was performed by the
Nottingham Clinical Research Group
(list online at http://www.jama.com).
The raw database was provided to the
TIMI Study Group and all analyses reported in this article were performed independently by the TIMI Study Group
(S.A.M.), whose members wrote this article and take responsibility for the data.
Validation of the major efficacy and
safety analyses was also performed by
Nottingham Clinical Research Group
(the data coordinating center), as well
as by the sponsor. Analyses were conducted by the TIMI Study Group by
using Stata SE version 9.0 (StataCorp
LP, College Station, Tex).
RESULTS
The 2 groups of patients were wellmatched with respect to their baseline
characteristics (TABLE 1). A total of
6303 patients (96.1%) were treated with
Table 1. Baseline Patient Characteristics*
Characteristics
Age, median (IQR), y
Age ⱖ75 y
Female sex
White race
Weight, median (IQR), kg
Body mass index, median (IQR)
Comorbidities
Diabetes mellitus
Hypertension
Hyperlipidemia
Current smoker
Cardiac history
Prior MI
Prior coronary revascularization
Prior heart failure
Estimated creatinine clearance ⬍60 mL/min†
Index event
Unstable angina
Non–ST-elevation MI
Other
ST-segment depression ⱖ0.1 mV
TIMI risk score‡
0-2
3-4
5-7
Time from onset of pain to randomization, median (IQR), h
Coronary angiography during the index hospitalization
Cardiac medications during index hospitalization
and/or discharge
Aspirin
Heparin
Glycoprotein IIb/IIIa receptor inhibitor
Thienopyridine
␤-Blocker
ACE inhibitor or angiotensin II receptor blocker
Statin
Ranolazine
Placebo
(n = 3279)
(n = 3281)
64 (55-72)
64 (56-72)
562/3279 (17.1)
592/3281 (18.0)
1106/3279 (33.7) 1185/3281 (36.1)
3112/3279 (94.9) 3129/3281 (95.4)
80 (72-92)
81 (71-91)
28 (25-31)
28 (25-32)
1104/3279 (33.7)
2395/3257 (73.5)
2028/3016 (67.2)
872/3276 (26.6)
1116/3281 (34.0)
2409/3258 (73.9)
2022/2982 (67.8)
804/3280 (24.5)
1119/3245 (34.5)
891/3277 (27.2)
538/3279 (16.4)
700/3265 (21.4)
1095/3251 (33.7)
853/3278 (26.0)
557/3281 (17.0)
702/3265 (21.5)
1541/3279 (47.0)
1675/3279 (51.1)
63/3279 (1.9)
1142/3279 (34.8)
1526/3281 (46.5)
1667/3281 (50.8)
88/3281 (2.7)
1162/3280 (35.4)
882/3279 (26.9)
884/3281 (26.9)
1727/3279 (52.7) 1730/3281 (52.7)
670/3279 (20.4)
667/3281 (20.3)
23.9 (13.3-34.1)
23.4 (13.4-34.4)
1937/3279 (59.1)
1935/3281 (59.0)
3154/3279 (96.2)
2989/3279 (91.2)
493/3279 (15.0)
2099/3279 (64.0)
2908/3279 (88.7)
2543/3279 (77.6)
2713/3279 (82.7)
3149/3281 (96.0)
2937/3281 (89.5)
462/3281 (14.1)
2116/3281 (64.5)
2944/3281 (89.7)
2587/3281 (78.9)
2691/3281 (82.0)
Abbreviations: ACE, angiotensin-converting enzyme; IQR, interquartile range; MI, myocardial infarction.
SI conversion: To convert creatinine clearance to mL/s, multiply by 0.0167.
*Data are expressed as No./total (%) unless otherwise specified.
†Estimated using Cockroft-Gault equation.
‡The TIMI risk score was used to categorize patients at low (0-2), intermediate (3-4), and high (5-7) risk.4
1778 JAMA, April 25, 2007—Vol 297, No. 16 (Reprinted)
aspirin, 5926 patients (90.3%) with
either unfractionated heparin or a lowmolecular-weight heparin, and 955 patients (14.6%) with a glycoprotein IIb/
IIIa receptor antagonist. The median
time from symptom onset to randomization was 24 hours (interquartile
range, 13-34). Study drug was administered intravenously to 6541 patients
(99.7%) for a median of 23 hours (interquartile range, 19-29) and followed
up with oral administration in 6399 patients (97.5%). The qualifying ACS was
managed with medical therapy alone in
3966 patients (60.5%), a percutaneous coronary intervention in 2074 patients (31.6%), and coronary artery bypass graft surgery in 520 patients
(7.9%). Concomitant medications were
administered to patients during the
treatment period as follows: clopidogrel or ticlodipine to 4215 patients
(64.3%); ␤-blockers to 5852 patients
(89.2%); calcium channel blockers to
1977 patients (30.1%), including diltiazem to 312 patients (4.8%) and verapamil to 190 patients (2.9%); angiotensin-converting enzyme inhibitors or
angiotensin II receptor blockers to 5130
patients (78.2%); and statins to 5404
patients (82.4%). Patients were followed for up to 24 months, with a median follow-up of 348 days (interquartile range, 236-460). Nine patients
(0.1%) were lost to follow-up.
Efficacy End Points
The primary end point (cardiovascular death, MI, or recurrent ischemia) occurred in 696 patients (21.8%) in the
ranolazine group compared with 753
patients (23.5%) in the placebo group
(HR, 0.92; 95% CI, 0.83-1.02; P=.11)
(FIGURE 2). The major secondary end
point (cardiovascular death, MI, or severe recurrent ischemia) occurred in
602 patients (18.7%) in the ranolazine group compared with 625 patients (19.2%) in the placebo group
(HR, 0.96; 95% CI, 0.86-1.08; P=.50).
Failure of therapy (cardiovascular
death, MI, recurrent ischemia, positive Holter for ischemia, hospitalization for new or worsening heart failure, or an early positive exercise
©2007 American Medical Association. All rights reserved.
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RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
at least 1 Canadian Cardiovascular Society Class requiring intensification of
medical therapy was reduced by ranolazine compared with placebo (135
[4.2%] vs 175 [5.9%]; HR, 0.77; 95%
CI, 0.62-0.97; P =.02). In addition, an
increase in or addition of antianginal
therapy was less frequent in the ranolazine group (316 [10.6%]) compared
with the placebo group (391 [13.0%];
HR, 0.80; 95% CI, 0.69-0.93; P=.003).
A small improvement in anginal frequency with ranolazine was recorded
using the Seattle Angina Question-
Figure 2. Kaplan-Meier Estimated Rates of the Primary End Point (Cardiovascular Death, MI,
or Recurrent Ischemia)
Cardiovascular Death, MI, or
Recurrent Ischemia, %
tolerance test) occurred in 1173 patients (36.8%) in the ranolazine group
compared with 1233 patients (38.3%)
in the placebo group (HR, 0.94; 95% CI,
0.87-1.02; P=.16).
Individual elements of the primary
end point and failure of therapy end
point at 30 days and end of study are
shown in TABLE 2. Ranolazine had no
effect on the rate of cardiovascular death
or MI, individually or as a composite
(FIGURE 3). However, the cumulative
incidence of recurrent ischemia was significantly lower in patients allocated to
ranolazine compared with those allocated to placebo (Figure 3). A trend toward an early reduction in recurrent ischemic complications with ranolazine
was evident with respect to the 30-day
end point of cardiovascular death, MI,
severe recurrent ischemia, or positive
Holter for ischemia (P=.055) (Table 2).
An effect of long-term treatment with
ranolazine on angina was evident with
respect to several prespecified exploratory end points. Worsening angina by
30
Placebo
Ranolazine
20
10
HR, 0.92 (95% CI, 0.83-1.02)
Log-Rank P = .11
0
180
360
540
Days After Randomization
No. at Risk
Placebo
Ranolazine
2454
2450
3281
3279
1223
1223
268
269
MI indicates myocardial infarction; HR, hazard ratio; CI, confidence interval.
Table 2. Efficacy Outcomes*
No. (%) of Patients
Randomization to end of study
Primary end point†
Major secondary end point‡
Cardiovascular death
MI
Recurrent ischemia
With electrocardiographic changes
Leading to hospitalization
Leading to revascularization
Worsening angina
Failure of therapy§
Hospitalization for heart failure
Randomization to 30 d
Cardiovascular death, MI, severe recurrent ischemia,
positive Holter for ischemia 㛳
Cardiovascular death
MI
Severe recurrent ischemia
Positive Holter for ischemia
Ranolazine
(n = 3279)
Placebo
(n = 3281)
P
Value
753 (23.5)
625 (19.2)
148 (4.5)
Risk
(95% CI)
Hazard Ratio
0.92 (0.83-1.02)
0.96 (0.86-1.08)
1.00 (0.79-1.25)
696 (21.8)
602 (18.7)
147 (4.4)
235 (7.4)
430 (13.9)
126 (4.1)
242 (7.6)
494 (16.1)
143 (4.7)
0.97 (0.81-1.16)
0.87 (0.76-0.99)
0.88 (0.69-1.12)
.76
.03
.31
247 (8.0)
142 (4.6)
135 (4.2)
1173 (36.8)
141 (4.5)
279 (8.8)
168 (5.3)
175 (5.9)
1233 (38.3)
135 (4.2)
.16
.13
.02
.16
.68
757 (23.1)
824 (25.1)
0.88 (0.75-1.05)
0.84 (0.67-1.05)
0.77 (0.62-0.97)
0.94 (0.87-1.02)
1.05 (0.83-1.33)
Relative Risk
0.92 (0.84-1.00)
57 (1.7)
90 (2.7)
121 (3.7)
50 (1.5)
114 (3.5)
131 (4.0)
1.14 (0.78-1.66)
0.79 (0.60-1.04)
0.92 (0.73-1.18)
.49
.09
.52
613 (19.9)
658 (21.0)
0.93 (0.84-1.04)
.21
.11
.50
.98
.055
Abbreviations: CI, confidence interval; MI, myocardial infarction.
*Reported values are hazard ratios for randomization to end of study and relative risks for randomization to 30 days. Event rates are Kaplan-Meier failure rates at 12 months.
Individuals may have experienced more than 1 event.
†Cardiovascular death, MI, or recurrent ischemia.
‡Cardiovascular death, MI, or severe recurrent ischemia.
§Cardiovascular death, MI, recurrent ischemia, hospitalization for new or worsening heart failure, positive Holter for ischemia, or an early positive exercise tolerance test.
㛳Prespecified 30-day end point.
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 25, 2007—Vol 297, No. 16
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1779
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
Figure 3. Kaplan-Meier Estimated Rates of Cardiovascular Death or MI and Recurrent Ischemia
Cardiovascular Death or MI
Recurrent Ischemia
30
Placebo
Ranolazine
Cumulative Percentage
Cumulative Percentage
30
20
10
20
10
HR, 0.99 (95% CI, 0.85-1.15)
Log-Rank P = .87
0
180
360
HR, 0.87 (95% CI, 0.76-0.99)
Log-Rank P = .03
540
0
Days After Randomization
No. at Risk
Placebo
Ranolazine
3281
3279
2711
2694
180
360
540
Days After Randomization
1458
1427
335
316
No. at Risk
Placebo
Ranolazine
3281
3279
2562
2570
1297
1307
296
295
MI indicates myocardial infarction; HR, hazard ratio; CI, confidence interval.
naire (mean [SD], 84.3 [22.2] in the
ranolazine group vs 82.2 [23.2] in the
placebo group; P⬍.001). This difference was greater among those patients
who entered the trial with a history of
angina (n = 2898 with Seattle Angina
Questionnaire data; mean [SD], 79.5
[24.1] in the ranolazine group vs 75.5
[25.3] in the placebo group; P⬍.001).
There was no difference in the physical limitation scale between treatment
groups in the overall population
(P=.91) or for those patients with prior
angina (P=.30).
There was no significant heterogeneity of the effect of ranolazine on the
primary end point across the major subgroups examined, including those patients treated with intent for a noninvasive strategy (FIGURE 4). In contrast
with previous studies suggesting diminished efficacy on exercise performance in women with stable angina,13
the effect of ranolazine on the primary
end point was significant among
women (n = 2291; HR, 0.83; 95% CI,
0.70-0.99), driven by a 29% relative reduction in recurrent ischemia with
ranolazine (P =.002), but without definitive statistical evidence of an interaction based on sex (P for interaction=.12). There was no heterogeneity
in the effect of ranolazine on recurrent ischemia in those patients treated
with an early invasive strategy compared with an early conservative strategy (P for interaction = .52).
Safety and Tolerability
Death from any cause in the safety analysis population did not differ among patients treated with ranolazine compared with patients treated with placebo
(HR, 0.99; 95% CI, 0.80-1.22; P=.91)
(TABLE 3). Sudden cardiac death and the
composite of death due to any cause or
any cardiovascular hospitalization also
did not differ in patients treated with
ranolazine (56 [1.7%] and 1046 [33.2%],
respectively) compared with those patients treated with placebo (65 [1.8%]
and 1082 [33.4%], respectively). The incidence of symptomatic documented arrhythmias throughout the duration of the
study was similar in patients treated with
ranolazine compared with placebo
(P=.84). Furthermore, the frequency of
clinically significant arrhythmias observed during Holter monitoring
(n=6351) during the first 7 days was
lower in the ranolazine group (2330 patients [73.7%]) vs in the placebo group
(2650 patients [83.1%], P⬍.001). This
reduction included a lower incidence of
ventricular tachycardia (948 [30%] of
3158 patients vs 1211 [38%] of 3184 patients, respectively; P⬍.001).
Discontinuation of treatment because of an adverse event, the patient’s
preference, or for other reasons occurred in 915 patients (28%) in the ranolazine group and 736 patients (22%) in
the placebo group (P⬍.001). Discontinuation due to an adverse event was reported significantly more frequently in
1780 JAMA, April 25, 2007—Vol 297, No. 16 (Reprinted)
patients receiving ranolazine (286
[8.8%]) compared with patients receiving placebo (154 [4.7%], P⬍.001). During treatment, the dose of study drug was
permanently decreased during the intravenous phase due to an adverse event
in 63 patients (1.9%) who were treated
with ranolazine and 37 patients (1.1%)
who were treated with placebo. In addition, in 13 patients (0.4%) in the ranolazine group, the dose was reduced for
renal dysfunction; in 31 patients (0.9%),
the dose was reduced for persistent prolongation of the QTc; and in 11 patients (0.3%), the dose was reduced for
other reasons. In the placebo group, each
of these proportions was 9 (0.3%), 10
(0.3%), and 11 (0.3%), respectively. During chronic treatment with oral study
medication, the dose was reduced in 334
patients (10%) receiving ranolazine and
in 177 patients (5%) receiving placebo
(P⬍.001). In the ranolazine group, the
last dose taken was 1000 mg twice daily
in 2715 patients (83%), 750 mg twice
daily in 180 patients (6%), 500 mg twice
daily in 235 patients (7%), and 375 mg
twice daily in 64 patients (2%); 74 patients (2%) never took an oral dose.
The most frequent adverse events,
which were not end points, occurred
in more than 4% of patients, and were
more frequent with ranolazine vs placebo, were dizziness (13% vs 7%), nausea (9% vs 6%), and constipation (9%
vs 3%, respectively). There were 109
cases of syncope in the ranolazine group
©2007 American Medical Association. All rights reserved.
Downloaded from www.jama.com on April 25, 2007
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
Figure 4. Kaplan-Meier Estimated Event Rates (12 Months) and HRs for the Primary End Point in the Ranolazine Group Compared With the
Placebo Group in Various Subgroups
No. of Events/Sample Size
Kaplan-Meier Rates, %
Subgroup
Ranolazine
Placebo
Ranolazine
Placebo
Sex
Men
464/2173
460/2096
21.8
22.3
0.98 (0.86-1.12)
232/1106
293/1185
21.8
25.8
0.83 (0.70-0.99)
Age, y
<75
538/2717
568/2689
20.3
21.6
0.93 (0.83-1.05)
≥75
158/562
185/592
29.2
32.5
0.90 (0.73-1.11)
431/2175
450/2165
20.2
21.4
0.95 (0.84-1.09)
265/1104
303/1116
25.0
27.7
0.87 (0.74-1.02)
239/1428
236/1450
17.4
16.2
1.03 (0.86-1.24)
443/1789
503/1776
25.2
29.4
0.86 (0.75-0.97)
300/1820
291/1781
17.4
16.5
1.01 (0.86-1.19)
396/1459
462/1500
27.4
31.8
0.87 (0.76-0.99)
324/1541
342/1526
21.4
23.1
0.94 (0.81-1.09)
364/1675
391/1667
22.4
24.2
0.92 (0.80-1.06)
416/2137
422/2118
20.1
20.4
0.97 (0.85-1.11)
280/1142
331/1162
25.0
29.2
0.85 (0.73-1.00)
Women
Diabetes Mellitus
No
Yes
Prior Angina
No
Yes
TIMI Risk Score∗
0-3
4-7
Index Diagnosis
Unstable Angina
Non–ST-Elevation MI
ST-Segment Depression ≥1 mm
No
Yes
Creatinine Clearance
≥60 mL/min
HR (95% CI)
485/2565
537/2563
19.2
21.3
0.90 (0.79-1.01)
<60 mL/min
208/700
212/702
31.5
31.6
0.98 (0.81-1.19)
Early Invasive†
No
444/1946
468/1947
23.2
24.9
0.94 (0.83-1.08)
Yes
252/1333
285/1334
19.7
21.6
0.88 (0.74-1.04)
Overall
696/3279
753/3281
21.8
23.5
0.92 (0.83-1.02)
Favors
Ranolazine
P for Interaction
Favors
Placebo
.12
.80
.39
.09
.16
.85
.23
.42
.52
0.5
1.0
2
HR (95% CI)
HR indicates hazard ratio; CI, confidence interval; MI, myocardial infarction. To convert creatinine clearance to mL/s, multiply by 0.0167.
*The TIMI risk score was dichotomized at the median, reflecting patients at higher (score 4-7) or lower (score 0-3) risk of death or recurrent ischemic events.
†Intent to manage the patient with an early invasive or conservative management strategy as recorded at the time of randomization.
(3.3%) and 75 cases in the placebo
group (2.3%, P=.01). These cases included events reported as syncope, vasovagal syncope, and loss of consciousness. The greater number of cases of
syncope in the ranolazine group (n=34)
were largely categorized by the investigator as vasovagal syncope (38 cases
vs 18 cases, respectively). Two cases of
torsades de pointes were identified by
the investigators: 1 in the placebo group
and 1 in the ranolazine group.
COMMENT
In this trial of patients with non−STelevation ACS at moderate to high risk
of recurrent cardiovascular events, there
was no significant benefit of ranolazine compared with placebo with re-
Table 3. Major Safety Outcomes*
No. (%) of Patients
Ranolazine
(n = 3268)
Death from any cause, by month
Placebo
(n = 3273)
Hazard Ratio
(95% CI)
P
Value
0.99 (0.80-1.22)
.91
.53
172
175
6
109 (3.4)
113 (3.5)
12
153 (5.3)
152 (5.1)
18
169 (7.0)
173 (7.4)
1046 (33.2)
1082 (33.4)
0.97 (0.89-1.06)
99 (3.0)
102 (3.1)
NA
.84
2330 (73.7)
2650 (83.1)
NA
⬍.001
Death or any cardiovascular
hospitalization
Symptomatic documented arrhythmia
Clinically significant arrhythmia
on Holter monitoring†
Abbreviations: CI, confidence interval; NA, not applicable.
*Safety analysis cohort (received ⱖ1 dose of study drug).
†Clincally significant arrhythmias on Holter were defined in the protocol as ventricular tachycardia of at least 100/min for 3
or more beats, supraventricular tachycardia of at least 120/min for 4 or more beats, bradycardia of less than 45/min,
pauses of more than 2.5 seconds, or third-degree heart block. Holter findings are expressed as a proportion among
those patients with Holter results (n = 3162 for the ranolazine group and n = 3189 for the placebo group). P values for
symptomatic documented arrhythmias and clinically significant arrhythmias on Holter are calculated by using the CochranMantel-Haenszel general association test stratified by the intention for early invasive management.
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 25, 2007—Vol 297, No. 16
Downloaded from www.jama.com on April 25, 2007
1781
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
spect to the composite end point of cardiovascular death, MI, or recurrent
ischemia during a median of 1 year of
treatment. Additional analyses revealed a 13% relative reduction in the
risk of recurrent ischemia, and fewer increases in other antianginal therapy in
patients treated with ranolazine, with
no effect on the composite of cardiovascular death or MI. Ranolazine appeared to be safe with no discernable
difference from placebo in the prespecified safety end points of symptomatic
documented arrhythmias, sudden cardiac death, or death from any cause. Indeed, ranolazine was associated with a
significant reduction in the frequency
of arrhythmias detected by Holter recording during the first 7 days after randomization. There was more syncope
reported with ranolazine, consonant
with the prior experience in patients
with chronic angina.7
Ranolazine is currently available for
the treatment of selected patients with
chronic angina who have persistent
symptoms despite treatment with
␤-blockers, calcium channel blockers,
or nitrates. Prior studies of ranolazine
extended-release have been conducted in patients with confirmed coronary artery disease with ischemic STsegment depression before completion
of 9 minutes on a modified Bruce protocol,5,6 or with at least 3 episodes of
angina per week despite treatment with
a calcium channel blocker.14 Together
these studies demonstrated that ranolazine increases the time to ischemia on
treadmill testing, improves exercise duration, and reduces the frequency of angina and use of sublingual nitroglycerin in these highly symptomatic
patients.7 Subgroup analyses from these
studies (approximately 1500 patients in
total) pointed to a possible diminished treatment effect of ranolazine on
exercise performance in women.13 Because of a concentration-related increase in the QT interval, the use of
ranolazine has been recommended only
for patients who have not had an adequate response to other antianginal
agents.7 Moreover, the sample size and
duration of therapy in these trials were
not designed to evaluate the effect of
ranolazine for secondary prevention of
major cardiovascular events. Experimental data have revealed reductions
in the extent of ischemic injury and improved left ventricular performance in
animal models with acute MI.15 However, ranolazine had not been studied
previously in patients with acute ischemic syndromes.
We enrolled patients during the acute
phase of their presentation with ACS
and investigated the efficacy of ranolazine for a potential new application
in the acute management of ACS as well
as for the long-term prevention of major cardiovascular events and recurrent ischemia. The results of this robustly powered, randomized trial do not
support the use of ranolazine for acute
management of ACS or as diseasemodifying therapy for secondary prevention of cardiovascular death or MI.
However, our findings suggest a benefit of ranolazine as antianginal therapy
in a substantially more broad population of patients with established ischemic heart disease than previously studied. Analyses of subgroups must be
interpreted cautiously given the overall nonsignificant primary efficacy result. Nevertheless, in contrast to prior
studies based on exercise testing, the
reduction in recurrent ischemia with
ranolazine was certainly not less in
women than in men.
In this large trial that approximately
doubles the existing safety experience
with ranolazine extended-release, we
found that there was no excess of
arrhythmias or sudden cardiac death
during a median 1-year follow-up in
patients treated with ranolazine compared with placebo. There was a
higher rate of discontinuation due to
adverse events in the ranolazine
group, with the most common adverse
events being dizziness, nausea, and
constipation. This tolerability profile
along with the higher proportion of
patients with syncope should be considered by the clinician in assessing
the potential risks vs benefits of treatment with ranolazine. The etiology of
syncope with ranolazine remains
1782 JAMA, April 25, 2007—Vol 297, No. 16 (Reprinted)
unexplained and requires additional
study.7 The finding of a significant
reduction in arrhythmias detected on
Holter monitoring during the first 7
days provides the first clinical evidence for the potential relevance of
experimental data showing suppression of markers of proarrhythmia,
including early after-depolarizations
and transmural dispersion of repolarization with ranolazine,16 and provides
some reassurance with respect to
arrhythmia as a potential cause for
syncope. Nevertheless, awareness with
longer term use in the community
remains important. The possible antiarrhythmic effects of ranolazine warrant additional investigation.
The following limitations of our study
should be recognized. All of the efficacy analyses reported in this article were
prespecified as part of the statistical
analysis plan that was finalized before
database lock. Given the statistically
nonsignificant result for the primary end
point, all additional efficacy analyses, although prespecified, should be considered as de facto exploratory. However,
particularly when interpreted in the context of prior randomized studies of ranolazine,5,6,14 our observations regarding
the efficacy and apparent safety of ranolazine as an antianginal agent contribute to an understanding of its clinical
use. The frequency of premature permanent cessation of study drug in our
trial is comparable with other contemporary trials of long-term therapy after
presentation with ACS.17,18 Premature
cessation of study drug would be expected to have biased the intention-totreat efficacy analysis toward the null
result.
CONCLUSIONS
The addition of ranolazine to current
standard of care for non−ST-elevation
ACS was not effective in reducing the
rate of the composite of cardiovascular death, MI, or recurrent ischemia, and
is not indicated for the treatment of
ACS. The observed reduction in recurrent ischemia in a broad population of
patients with established coronary artery disease is consistent with previ-
©2007 American Medical Association. All rights reserved.
Downloaded from www.jama.com on April 25, 2007
RANOLAZINE IN NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
ous evidence in selected patients with
chronic angina. These findings, together with the observed favorable overall profile of safety, provide additional
evidence to guide the use of ranolazine as antianginal therapy in patients
with chronic angina.
Author Affiliations: TIMI Study Group, Department
of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass (Drs Morrow,
Scirica, and Braunwald, and Mss Murphy and McCabe);
CV Therapeutics, Palo Alto, Calif (Dr KarwatowskaProkopczuk); Postgraduate Medical School, Department of Cardiology, Grochowski Hospital, Warsaw,
Poland (Dr Budaj); Evidence Clinical and Pharmaceutical Research, St Petersburg, Russia (Dr Varshavsky); Cytokinetics, San Francisco, Calif (Dr Wolff );
and Nottingham Clinical Research Limited, Nottingham, United Kingdom (Dr Skene).
Author Contributions: Drs Morrow and Braunwald and
Ms Murphy had full access to all the data in the study
and take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Morrow, KarwatowskaProkopczuk, Wolff, Skene, McCabe, Braunwald.
Acquisition of data: Morrow, Scirica, Skene, McCabe,
Braunwald.
Analysis and interpretation of data: Morrow, Scirica,
Karwatowska-Prokopczuk, Murphy, Budaj, Varshavsky,
Wolff, Skene, McCabe, Braunwald.
Drafting of the manuscript: Morrow, Braunwald.
Critical revision of the manuscript for important intellectual content: Morrow, Scirica, KarwatowskaProkopczuk, Murphy, Budaj, Varshavsky, Wolff, Skene,
McCabe, Braunwald.
Statistical Analysis: Murphy, Skene.
Obtaining funding: Morrow, McCabe, Braunwald.
Administrative, technical or material support: Morrow,
Scirica, Karwatowska-Prokopczuk, Murphy, Skene,
McCabe, Braunwald.
Study Supervision: Morrow, McCabe, Braunwald.
Financial Disclosures: The TIMI Study Group reports
receiving significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare,
Beckman Coulter, Biosite, Bristol-Myers Squibb, CV
Therapeutics, Eli Lilly, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck & Co,
Merck-Schering Plough Joint Venture, Millennium
Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo,
Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, and ScheringPlough. Dr Morrow reports receiving honoraria
for educational presentations from CV Therapeutics
and Sanofi-Aventis, serving as a consultant for
GlaxoSmithKline and Sanofi-Aventis, and being on an
advisory board for Genentech. Dr Scirica reports receiving honoraria for educational presentations from
CV Therapeutics. Dr Karwatowska-Prokopczuk is an
employee of and owns stock in CV Therapeutics. Dr
Budaj reports receiving honoraria from AstraZeneca,
CV Therapeutics, GlaxoSmithKline, and SanofiAventis, and serving as a consultant to GlaxoSmithKline
and Sanofi-Aventis. Dr Varshavsky reports receiving
research grant support from CV Therapeutics. Dr Wolff
is a former employee of CV Therapeutics and currently serves as a consultant as well as holding stock/
options in CV Therapeutics, and he reports being
named on patents for ranolazine. Dr Braunwald reports receiving honoraria from and serving as a consultant to AstraZeneca, Bayer AG, Daichii Sankyo,
Merck, Pfizer, and Schering-Plough. Dr Skene and Mss
Murphy and McCabe did not report any disclosures.
Funding/Support: The MERLIN-TIMI 36 trial was
funded by CV Therapeutics.
Role of the Sponsor: The protocol was developed by
the TIMI Study Group in conjunction with the steering committee and review by the trial sponsor. Employees of the sponsor worked with the investigators
to prepare the statistical analysis plan. All primary analyses were performed by the TIMI Study Group with validation by Nottingham Clinical Research and the sponsor. Employees of the sponsor reviewed the manuscript
together with the coauthors and made nonbinding suggestions for edits.
Independent Statistical Analysis: The investigators had
free and complete access to the data. Data coordination was performed by the Nottingham Clinical Research Group (see online appendix). The raw database was provided to the TIMI Study Group and all
analyses reported in this manuscript were performed
independently by the TIMI Study Group (Ms Murphy), whose members wrote this article and take responsibility for the data. Validation of the major efficacy and safety analyses was also performed by
Nottingham Clinical Research (the data coordinating
center), as well as by the sponsor.
MERLIN-TIMI 36 Study Investigators appear online
at http://www.jama.com.
ischemic effects and long-term survival during
ranolazine monotherapy in patients with chronic
severe angina. J Am Coll Cardiol. 2004;43:1375-1382.
7. Chaitman BR. Ranolazine for the treatment of
chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113:2462-2472.
8. Belardinelli L, Shryock JC, Fraser H. Inhibition of
the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006;92(suppl 4):iv6-iv14.
9. Morrow DA, Scirica BM, Karwatowska-Prokopczuk
E, Skene A, McCabe CH, Braunwald E. Evaluation
of a novel anti-ischemic agent in acute coronary
syndromes: design and rationale for the Metabolic
Efficiency with Ranolazine for Less Ischemia
in Non-ST-elevation acute coronary syndromes
(MERLIN)-TIMI 36 trial. Am Heart J. 2006;152:400406.
10. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a
report of the American College of Cardiology Task
Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001;
38:2114-2130.
11. Spertus JA, Jones P, McDonell M, Fan V, Fihn
SD. Health status predicts long-term outcome in outpatients with coronary disease. Circulation. 2002;106:
43-49.
12. Fleming TR, Harrington DP, O’Brien PC. Designs for group sequential tests. Control Clin Trials.
1984;5:348-361.
13. Wenger NK, Chaitman B, Vetrovec GW. Gender
comparison of efficacy and safety of ranolazine for
chronic angina pectoris in four randomized clinical trials.
Am J Cardiol. 2007;99:11-18.
14. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ,
Meng L. Antianginal efficacy of ranolazine when added
to treatment with amlodipine: the ERICA (Efficacy of
Ranolazine in Chronic Angina) trial. J Am Coll Cardiol.
2006;48:566-575.
15. Gralinski MR, Black SC, Kilgore KS, Chou AY,
McCormack JG, Lucchesi BR. Cardioprotective effects of ranolazine (RS-43285) in the isolated perfused rabbit heart. Cardiovasc Res. 1994;28:
1231-1237.
16. Antzelevitch C, Belardinelli L, Zygmunt AC, et al.
Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
Circulation. 2004;110:904-910.
17. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:
1495-1504.
18. de Lemos JA, Blazing MA, Wiviott SD, et al. Early
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©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, April 25, 2007—Vol 297, No. 16
Downloaded from www.jama.com on April 25, 2007
1783
WEB-ONLY CONTENT
MERLIN-TIMI 36 Study Group: Brigham and Women’s Hospital, Boston, Mass: Eugene Braunwald (study
chairman), Carolyn H. McCabe (director), David A.
Morrow (principal investigator), Benjamin M. Scirica
(coinvestigator), Susan McHale (project manager),
Sabina A. Murphy and Jacqueline Buros (statistical
group).
Data Coordinating Center, Randomization, and Site
Management Outside North America: Nottingham
Clinical Research Group, Nottingham, United Kingdom: Allan Skene (managing director), Karen Hill (head
of project management), Andrew Kempton and
Elizabeth Jenkins (project managers), Philip Sparks (statistics).
CV Therapeutics, Palo Alto, Calif (Sponsor): Brent
Blackburn (head of clinical research and development), Ewa Karwatowska-Prokopczuk (clinical research), Peter Strumph (head of clinical operations),
Nancy Vinh and Rod van Syock (clinical operations),
Michael Crager, Sandra Dixon, Lindley Frahm, and Efim
Dynin (statistics), Jason Carlson and Susan Krikorian
(data management), Anne Champsaur and Ann
Dingerson (drug safety), Luiz Belardinelli (clinical pharmacology).
Steering Committee: Members of the TIMI Study
Group, Data Coordinating Center, and Sponsor, plus
Philip Aylward (Australia); Jean-Pierre Bassand (France);
Christoph Bode (Germany); Andrzej Budaj (Poland);
John Camm (United Kingdom); Bernard Chaitman (US);
Arturo Cortina (Espana); Anthony Dalby (South Africa);
James deLemos (US); Bernard Gersh (US); Judith
Hochman (US); Hanoch Hod (Israel); Kurt Huber (Austria); Spencer King (US); Neal Kleiman (US); Jose LopezSendon (Spain); Thomas Luscher (Switzerland); Attilio
Maseri (Italy); Piera Merlini (Italy); Peter Molhoek (the
Netherlands); Lionel Opie (South Africa); Erika Ostor
(Hungary); Bertram Pitt (US); Jeffrey Popma (US);
Burton Sobel (US); Jindrich Spinar (Czech Republic);
Peter Stone (US); Pierre Theroux (Canada); Frans Van
de Werf (Belgium); Sergei Varshavsky (Georgia and
Russia); Freek Verheugt (the Netherlands); Harvey
White (New Zealand); Robert Wilcox (United Kingdom).
Data and Safety Monitoring Board: Joseph Alpert
(chairman), Michel Bertrand, Keith A. A. Fox, L. David
Hillis, Sheryl F. Kelsey.
Independent Statistical Group: Clinimetrics, San Jose,
Calif.
Clinical Events Committee: Stephen D. Wiviott (chairman), Clifford Berger, Carolyn Ho, David E. Leeman,
Mark Link, Henry P. Lyle, William Maisel, Pinak Shah.
Core Laboratories: Biomarker: TIMI Biomarker Core
Laboratory, Brigham and Women’s Hospital, Boston,
Mass; David A. Morrow, Nader Rifai. Continuous ECG
(Holter): TIMI Ambulatory ECG Core Laboratory,
Brigham and Women’s Hospital, Boston, Mass;
Benjamin M. Scirica, Julian Aroesty, Roger White. ECG
(Exercise Tolerance Testing): St Louis University, St
Louis, Mo; Bernard Chaitman.
Participating Enrolling Centers (No. of patients enrolled in each country): Austria (50 patients): National lead investigator: K. Huber. D. Cilesiz, S. Hahne,
Wilhelminenspital, Wien; H. Drexel, T. Kathrein,
Landeskrankenhaus, Fedkirch; G. Christ, K. Katsaros,
Allgemeines Krankenhaus, Wien; A. Podczeck, E.
Schmidt, Kaiser-Franz-Joseph Spital, Wien; H. Frank,
T. Kircher, Landesklinikum Donauregion, Tulln; T.
Stefenelli, M. Schäfer, Kaiserin-Elisabeth-Spital, Wien.
Belgium (149 patients): National lead investigator: F.
Van der Werf. P. Van Iseghem, E. Dhondt, StRembertziekenhuis, Torhout; B. Wollaert, G. Debaecke,
Ziekenhuis Netwerk Antwerpen, Antwerpen; R.
Beeuwsaert, V. Colpaert, H. Hartziekenhuis, Roeselare;
W. Van Mieghem, E. Volders, Ziekenhuis
Oost-Limburg, Genk; F. Loth, J. Geraedts, AZ SintBlasius, Dendermonde; J. Thoeng, J. Cauwenberghs,
Sint-Elisabethziekenhuis, Turnhout; R. Popeye, J.
Peperstraete, Sint-Augustinuskliniek, Veurne; L. De
Wolf, C. Brike, AZ H.Hart, Tienen; S. Hellemans, N.
Simons, AZ Klina, Brasschaat; M. Eycken, P. Huygen,
AZ Sint-Augustinus, Wilrijk; J. Roosen, C. Van
Goethem, Imelda Ziekenhuis, Bonheiden; H. Celen,
E. Wendelen, Regionaal Ziekenhuis H. Hart, Leuven;
B. Pirenne, Clinique Saint-Pierre, Ottignies.
Canada (382 patients): National lead investigator: P.
Theroux. R. Bhar gava, A. McCallum, Lakeridge Health
Oshawa, Ontario; S. Kouz, M. Roy, Central Hospitalier Regional de Lanaudiere, Quebec City; S. Vizel,
P.D. Solomon, Cambridge Memorial Hospital, Ontario; T. Rebane, H. Hink, Trillium Health Centre,
Mississauga Site, Ontario; J. Bhatt, D. Brennan, Brockville General Hospital, Ontario; W. P. Klinke, N.
Lounsbury, Victoria General Hospital, British Colombia; L. Bilodeau, N. St. Jean, Montreal Heart Institute, Quebec; C. Lai, S. Chisholm, Thunderbay Regional Hospital−Port Arthur, Ontario; J. Heath, L. Scott,
Campbell River and District Hospital, British Colombia; D. Cleveland, S. Valley, Penticton Regional Hospital, British Colombia; T. Huynh, C. Bondreault, Montreal General Hospital, Quebec; G. Houde, S. Dube,
CHA. Hopital de L’enfant-Jesus, Quebec; E. Lonn, B.
Miller, Hamilton Health Sciences, Ontario; G. Gosselin,
M. David, C.H. Pierre Le Gardeur, Quebec; P. Polasek,
L. Turri, Kelowna General Hospital, British Colombia;
S. Lepage, D. Soucy, CHUS Fleurimont, Quebec; B.
Tremblay, C. Darveau, CHUQ-Hotel Dieu de Quebec, Quebec; D. Grandmont, D. Carignan, CSSS
Richelieu Yamaska, Quebec; F. Grondin, F. Dumont,
Hotel-Dieu de Levis, Quebec; R. Haichin, V. Toyota,
Royal Victoria Hospital, Quebec; Y. Pesant, V. Sardin,
St. Jerome Medical Center, Quebec; M. LeMay, A.
Feres, University of Ottawa Heart Institute, Ontario;
R. H. Zimmermann, G. Patterson, Regina General Hospital, Saskatchewan; A. H. Lipson, J. Winestock, Victoria General Hospital, Manitoba; A. H. Lipson; Y. K.
Chan, D. Zaniol, Niagra Health System−Niagara General Site, Ontario; J. Picard, D. Couture, Hopital HotelDieu Sorel, Quebec; J. Hansen, B. Hodder, Foothills
Hospital; W. Sobkowski, L. Collins, Niagra Health
System−Welland Site, Ontario; D. C. Phaneuf, C.
LeMay, Hotel−Dieu de Montreal, Quebec; R. M.
Iwanochko, D. Tuttle, University Health Network
Toronto General Hospital, Ontario; J. Pouliot, S.
Marquette, CH Val-d’or, Quebec; B. Lubelsky, D.
Dejewski, North York General Hospital, Ontario; R.
M. Iwanochko, J. Renton, University Health Network Toronto Western Hospital, Ontario.
Czech Republic (392 patients): National lead investigator: J. Spinar. F. Holm, V. Hraboš, Regional Hospital Liberec, Liberec; B. Janek, V. Karmazin, Institute
for Clinical and Experimental Medicine, Praha; J. Navrátil, L. Francek, Hospital Kroměřı́ž, Kroměřı́ž; O. Mayer,
Jr, University Hospital Plzeň, Plzeň-Bory; M. Pěnička,
R. Jirmář, Charles University Hospital Kralovske Vinohrady, Praha; O. Toman, J. Pařenica, University Hospital Brno, Brno; V. Mrázek, J. Bělohlávek, General University Hospital (2nd Internal Department of Cardiology
and Angiology), Praha; J. Malik, J. Šimek, General University Hospital (3rd Department of Internal Medicine), Praha; J. Matoušková, O. Aschermann, Na Homolce Hospital, Praha; R. Pudil, R. Pelouch, University
Hospital Hradec Králové, Králové; M. Souček, J. Špác,
St Anne’s University Hospital in Brno (2nd Department of Internal Medicine), Brno; J. Vı́tovec, B.
©2007 American Medical Association. All rights reserved.
Fischerová, St Anne’s University Hospital in Brno (1st
Department of Cardioangiology), Brno; Z. Klimsa, M.
Holub, Hospital Jihlava, Jihlava; V. Rozsı́val, Regional
Hospital Pardubice, Pardubice.
France (61 patients): National lead investigator: J-P.
Bassand. S. Alsagheer, Hôpital de la SSM, FreymingMerlebach; E. Decoulx, Centre Hospitalier Gustave
Dron, Tourcoing; J-L. Roynard, Centre Hospitalier Général de Dax, Dax; F. Leroy, Centre Hospitalier de Douai,
Douai; P. Legalery, K. Petit-Didier, Hôpital Jean Minjoz, Besancon; J-E. Poulard, Centre Hospitalier, Abbeville; A. Rifai, Centre Hospitalier d’Arras, Arras; P.
Geslin, V. Valin, CHU d’Angers, Angers; J-L. Bonnet,
C. Mielot, Hôpital de la Timone, Marseille; E. Ferrari,
C. Moisan, Hôpital Pasteur, Nice.
Georgia (490 patients): National lead investigator: S.
Varshavsky. B. Kobulia, I. Jashi, Institute of Cardiology, Tbilisi; N. Emukhvari, I. Khintibidze, Clinic #1 Tbilisi
State Medical University, Tbilisi; V. Chumburidze, T.
Kikalishvili, National Center of Therapy, Tbilisi; K.
Paposhvili, M. Shushania, Multiprofile Clinical Hospital of Tbilisi #2, Tbilisi; T. Shaburishvili, G.
Ckhabeishvili, Diagnostic Services Clinic, Tbilisi; G.
Chapidze, L. Rigvava, Emergency Cardiology Centre, Tbilisi; M. Mamatsashvili, S. Rtskhiladze, Clinic of
Angiocardiology “ADAPTI,” Tbilisi.
Germany (333 patients): National lead investigator:
C. Bode. C. von zur Mühlen, J. Lohrmann, Universitätsklinikum, Freiburg; K. Nogai, R. Gorgas, Havelland
Klinik Nauen, Nauen; W. Leupolz, Y. Hernandez,
Klinik Oberstdorf der Kliniken Oberallgäu gGmbH,
Oberstdorf; W. Spitzer, Kreiskrankenhaus Neustadt,
Neustadt; R. Cardoso, Kreiskrankenhaus Eschwege,
Eschwege; C. Nienaber, O. Thiele, Universitätsklinikum, Rostock; M. Ferrari, M. Görnig, Universitätsklinikum Jena, Jena; H. Haun, Agnes-Karll-Krankenhaus,
Laatzen; M. Meuser, J. Singh, Malteser Krankenhaus, Juelich; W. Lepper, A. Kersten, Universitätsklinikum RWTH Aachen, Aachen; H. Katus, E. Giannitsis,
Universitätsklinikum, Heidelberg; H. Jablonowski, T.
Pastuszak, Städt. Krankenhaus Salzgitter Lebenstedt,
Salzgitter; S. Lüders, U. Venneklaas, St Josef Hospital, Cloppenburg; H. Hust, J. Haas, Klinikum am
Steinberg, Reutlingen; J. Cyran, M. Ackermann, Klinikum am Gesundbrunnen, Heilbronn; R. Beythien, C.
Bosch, St Sixtus Hospital, Haltern; J. Engel, C. Heuser,
Krankenhaus Links der Weser, Bremen; H. Bechtold,
Kreiskrankenhaus, Crailsheim; P. Lenga, M. Tyssen,
St Vincenz Krankenhaus, Datteln; R. Erbel, S. Philipp,
Westdeutsches Herzzentrum, Essen; R. Zotz, M.
Schulze, Schwalm-Eder-Kliniken, Schwalmstadt; G.
Meinhardt, M. Offterdinger, Robert-BoschKrankenhaus, Stuttgart; G. Baumann, V. Stangl, Charite
Campus Mitte, Berlin; W. Sehnert, M. Katz, Evangelisches Krankenhaus, Herne; H. Ochs, C. Spannagel,
Marienkrankenhaus, Soest; F. Kalbitz, E. Schlenzig,
Städtisches Krankenhaus Martha-Maria, HalleDölau; A. Schärtl, St Vincenz-Krankenhaus, Paderborn; A. Schmidt, S. Heißler, Klinikum Heidenheim,
Heidenheim; B. Kohler, S. Wagner, Krankenhaus Bruchsal, Bruchsal; F. Hartmann, C. Lindermann, Universitätsklinikum, Lübeck; A. van de Loo, M. Thiel, Marienkrankenhaus Hamburg, Hamburg; M. Sternkopf, J.
Kuntsche, Kreiskrankenhaus Friedberg, Friedberg; T.
Horacek, A. Eckartz, Evangelisches Krankenhaus, Witten; D. Lamotte, Herzzentrum, Leipzig; E. Boudroit;
T. Dorsel, N. Wistorf, St Josephs Hospital, Warendorf; P. Tilhein, Kreiskrankenhaus, Gifhorn; P. Schuster,
C. Beythien, St Marienkrankenhaus, Siegen; H.
Schultheiss, B. Witzenbichler, Charité Campus Benjamin Franklin, Berlin; G. Gehling, M. Simons, St Johannes Krankenhaus, Hagen; K. Werdan, H. Ebelt,
(Reprinted) JAMA, April 25, 2007—Vol 297, No. 16
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WEB-ONLY CONTENT
Universitätsklinikum Martin-Luther, Halle; W.
Franz, S. Brunner, Klinikum der LMU MünchenGrosshadern, München; H. Heuer, M. Schulz,
St-Johannes Hospital, Dortmund.
Hungary (253 patients): National lead investigator: E.
Östör. J. Tenczer, A. Kerkovits, Szt. Imre Korhaz, Budapest; P. Kárpáti, Z. Davidovits, Szt. Istvan Korhaz, Budapest; A. Janosi, B. Kiss, Szt. Janos Korhaz, Budapest;
L. Király, Kozponti Honved Korhaz, Budapest; A. Nagy,
M. Bosko, Bacs-Kiskun Megyei Korhaz, Kecskemét;
Z. Kovacs, I. Gyetvai. Bajai Korhaz, Bajai; M. Sereg,
A. Badics, Szt. Gyorgy Megyei Korhaz, Székesfehérvár;
Z. Bogdan, C. Kato, Pándy Kálmán Korhaz, Gyula; A.
Katona, F. Erdei, Keszthelyi Varosi Korhaz,
Keszthely.
Israel (531 patients): National lead investigator: H. Hod.
A. Marmor, I. Levin, Rebecca Sieff Medical Center,
Safed; Z. Vered, G. Moravsky, Assaf Harofeh Medical
Center, Zerifin; L. Reisin, T. Drogenikov, Barzilai Medical Center, Ashkelon; O. Kracoff, N. Roitberg, Kaplan
Medical Center, Rehovot; B. Lewis, R. Yuval, Carmel
Medical Center, Haifa; S. Matetzky, P. Fefer, Chaim
Sheba Medical Center, Tel Hashomer; Y. Rozenman,
B. Klaiman, Wolfson Medical Center, Holon; D. Zahger,
S. Kobal, Soroka Medical Center, Beer Sheva; U.
Rosenschein, Z. Gasan, Bnai Zion Medical Center, Haifa;
M. Mosseri, Y. Khudyak, Sapir Medical Center, Kfar
Saba; A. Battler, A. Porter, Rabin Medical Center, Petach
Tikva; H. Hammerman, T. Arditi, Rambam Medical Center, Haifa; S. Viskin, D. Zeltser, Sourasky Medical Center, Tel-Aviv; M. Klutstein, M. Moriel, Shaare Zedek
Medical Center, Jerusalem; N. Roguin, A Qrivilevich,
Western Galilee Hospital, Nahariya.
Italy (419 patients): National principal investigator: P.
Merlini. P. Merlini, Ospedale Niguarda Cà Granda, Milano; A. Vetrano, A. D’Onofrio, Azienda Ospedaliera
Ospedale San Sebastiano, Caserta; G. De Ferrari, A.
Mazzuero, Pavia Policlinico San Matteo, Pavia; O.
Silvestri, A. Sasso, A.O.R.N. Antonio Cardarelli, Napoli;
S. Pirelli, B. Fadin, Azienda Ospedaliera Istituti Ospitalieri di Cremona, Cremona; M. Galli, A. Menegato,
Presidio Ospedaliero Zona di Livorno, Livorno; A. Rolli,
D. Lina, Parma Azienda Ospedaliera di Parma, Parma;
V. Ciconte, D. Giancotti, Ospedale “A. Pugliese”, Catanzaro; A. Salvioni, F. Susini, Fondazione Monzino,
I.R.C.C.S. S.P.A., Milano; R. Evola, N. Russo, Taormina
Ospedale San Vincenzo, Taormina; A. Fiscella, M.
Giacoppo, Azienda Ospedale Cannizzaro, Catania; G.
Carmina, G. Celona, Azienda Ospedaliera Vincenzo
Cervello, Palermo; E. Corrada, M. Rossi, Istituto Clinico
Humanitas, Rozzano; F. Miccoli, S. Ubaldi, Presidio Ospedaliero Sanremo, Sanremo; A. Marzari, F. Mistrorigo,
Policlinico Universitario, Padova; M. Comito, P. Maglia,
Ospedale G. Jazzolino, Vibo Valentia; F. Cariello, Istituto Ninetta Rosano Clinica Tricarico, Belvedere Marittimo; E. Murena, V. Grassia, Ospedale Civile Santa
Maria delle Grazie, Pozzuoli; S. Domenicucci, M.
Merello, Ospedale Padre Antero Micone, Genoa Sestri
P; A. Pessina, Ospedale San Raffaele, Milano; D.
Cianflone, F. Fusco, B. Corlianò, Ospedale Policlinico
Consorziale, Bari; M. Giannetto, C. Nipote, Azienda
Ospedaliera Universitaria G. Martino, Messina; P.
Delise, G. Turiano, Ospedale Santa Maria dei Battuti,
Conegliano; C. Tamburino, G. Licciardello, Ospedale
Ferrarotto, Catania; M. Di Biase, C. Distaso, Ospedali
Riuniti A.O. Università di Foggia, Foggia; P. Assennato,
F. Scordato, A.O. Universitaria Policlinico Giaccone,
Palermo; P. Terrosu, G. Contini, Ospedale Civile S.S.
Annunziata, Sassari; R. Fanelli, A. Facciorusso, Ospedale Casa Sollievo della Sofferenza, San Giovanni
Rotondo; L. Fattore, M. De Divitiis, Ospedale S. Giuseppe e Melorio, S. Maria Capua Vetere; B.
D’Alessandro, A. Andriani, Ospedale Civile di Policoro, Policoro.
The Netherlands (547 patients): National lead investigators: F. Verheugt and P. Molhoek. F. Visser, E.
Geerligs, VU Medisch Centrum, Amsterdam; J. ten
Berg, M. Bosschaert, St Antonius Ziekenhuis, Nieu-
wegein; J. Herrman, F. Bosman, Onze Lieve Vrouwe
Gasthuis, Amsterdam; V. Umans, S. Schrijver-van
Velthoven, Medisch Centrum Alkmaar, Alkmaar; A.
Funke Kupper, C. Kalkman, Kennemer Gasthuis EG,
Haarlem; A. Withagen, J. Kooistra-Huizer, Reinier de
Graaf Gasthuis, Delft; E. de Melker, St Lucas Andreas
Ziekenhuis, Amsterdam; B. Hamer, T. Wildbergh, Meander Medisch Centrum, Amersfoort; P. Bendermacher,
H. Heijmen, Elkerliek Ziekenhuis, Helmond; A. Oude
Ophuis, D. Hertzberger, Canisius-Wilhelmina Ziekenhuis, Nijmegen; D. Odekerken, M. Schiks, Spaarne
Ziekenhuis, Hoofddorp; R. Robles de Medina, C. de
Jonge, Haga Ziekenhuis, Den Haag; W. Agema, E.
Badings, Deventer Ziekenhuis, Deventer; J. Winter,
Tweesteden Ziekenhuis, Tilburg; M. Dirks, I. Roozen,
Medisch Centrum Rijnmond-Zuid, Rotterdam; C. Dille,
P. Leemans, Medisch Centrum Haaglanden, Den Haag;
H. de Lange, P. van Dijkman, Ziekenhuis Bronovo, Den
Haag; L. Bartels, M. Hendriks, Scheper Ziekenhuis, Emmen; J. Westenberg, W. Veenstra, Martini Ziekenhuis, Groningen; H. Louwerenberg, H. van Maarsenveen-Wolters, Medisch Spectrum Twente, Enschede;
J. Kruik, A. Pieterse, Ziekenhuisgroep Twente, Almelo;
L. van Loo, W. Smits, Maasziekenhuis Pantein, Boxmeer; A. Oomen, H. Swart, Antonius Ziekenhuis,
Sneek; J. Verheul, L. Konijnenberg, Flevoziekenhuis,
Almere; I. Hendriks, B. van den Berg, IJsselland Ziekenhuis, Capelle a/d IJssel; H. Thijssen, M. Beganovich, Maxima Medisch Centrum, Veldhoven; R. van
Stralen, M. van der Zeist, Ziekenhuis Gooi Noord, Blaricum; R. Dijkgraaf, C. van der Horst, Ziekenhuis St Jansdal, Harderwijk; G. Jochemsen, C. van Daalen, Ziekenhuis De Tjongerschans, Heerenveen; A. Dall ‘Agata,
F. den Hartog, Ziekenhuis Gelderse vallei, Ede; J.
Kragten, A. Boehmer, Atrium Medisch Centrum,
Heerlen; P. Nierop, M. van der Knaap, St Franciscus
Gasthuis, Rotterdam; W. Hermans, J. de Grauw, St
Elisabeth Ziekenhuis, Tilburg; A. Schaap, M. Beijering, Streekziekenhuis Coevorden-Hardenberg, Hardenberg; P. de Milliano, Ziekenhuis Hilversum, Hilversum; J. Tans, J. Aalders, Gemini Ziekenhuis, Den Helder;
E. Göbel, C. Werter, Laurentius Ziekenhuis, Roermond; C. van der Zwaan, J. Havenaar, Ziekenhuis Rivierenland, Tiel; H. Werner, M. Wittekoek, Vlietland
Ziekenhuis, Schiedam; J. Geertman, A. Stallinga, Diaconessenhuis Meppel, Meppel; R. Ciampricotti, S.
Ottenheijm, Ziekenhuis Zeeuws-Vlaanderen,
Terneuzen.
Poland (588 patients): National lead investigators: A.
Budaj, J. Gessek. B. Bednarz, P. Kokowicz, Szpital Grochowski, Warszawa; J. Rekosz, J. Biegajło, Wojewodzka Stacja Pogotowia Ratunkowego, Warszawa; M.
Stopiński, P. Komorowski, SZPZOZ Szpital Zachodni
im. Jana Pawla II, Grodzisk Mazowiecki; T.
Kawka-Urbanek, P. Wojewoda, Wojewodzki Szpital
Zespolony, Skierniewice; P. Mie˛kus, J. Błaszak, Szpital Miejski w Gdyni, Gdynia; M. Szpajer, M.
Wróblewska, Szpital Morski im. PCK, Gdynia; W.
Krasowski, D. Sendrowski, Szpital Specjalistyczny św.
Wojciecha-Adalberta, Gdańsk; M. Piepiorka, A. Priebe,
Szpital Specjalistyczny w Wejherowie, Wejherowo;
M.Trusz-Gluza, K. Wita, Samodzielny Publiczny Szpital Kliniczny SAM GCM, Katowice; P. Buszman, B.
Białkowska, GCM Slaskiej Akademii Medycznej,
Katowice; J. Wodniecki, A. Tomasik, Slaska Akademia Medyczna, Zabrze; M. Krauze-Wielicka, J. Spyra,
SPZOZ Szpital Miejski nr 2, Ruda Śla˛ska; W. Pluta, P.
Jasionowicz, PS ZOZ Wojewodzkie Centrum Medyczne, Opople; R. Szelemej, M. Górski, Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego, Walbrzych; S. Malinowski, M.Michalczyk, SP ZOZ im. J.
Smniadeckiego, Nowy Sa˛cz; A. Kleinrok, J. Rodzik, Szpital Wojewodzki im. Jana Pawla II, Zamość; M.
Ogórek, D. Kopcik, Samodzielny Szpital Wojewodzki, Piotrków Trybunakski; K. Janik, E. Gajda, SPZOZ
Szpital Miejski Szpital Zespolony, Cze˛stochowa; Z. Zieliński, U. Klekowska, Szpital Powiatowy w Radomsku, Radomsko; L. Pawłowicz, G. Pietrzkowicz, Spec-
E2 JAMA, April 25, 2007—Vol 297, No. 16 (Reprinted)
jalistyczny Szpital Miejski im. M. Kopernika, Toruń; M.
Bronisz, Ł. Oleśkowska, Oddzial Kardiologiczny PS
ZOZ, Inowroclaw; T. Siminiak, A. Bolewski, Szpital
Wojewódzki w Poznaniu, Poznań; F. Monies, J. Gniot,
Szpital Specjalistyczny Oddzial Kardiologii, Pulawy.
Russia (762 patients): National lead investigator: S.
Varshavsky. V. Kostenko, E. Skorodumova, St. Petersburg Dzhanelidze Research Institution, St Petersburg; B. Goloschekin, A. Lupikhin, City Hospital No.
15, St Petersburg; O. Orlikova, E. Orlikov, Saratov Research Institute of Cardiology of Federal Agency for
Healthcare and Social Development, Saratov; M.
Karpenko, N. Burova, Almazov Research Institute of
Cardiology, St Petersburg; Y. Shwarts, R. Lyubeznov, Saratov State Medical University, Saratov; L.
Sorokin, I. Koval, City Hospital of Saint Martyr Elizabeth, St Petersburg; A. Vishnevsky, D. Kositsyn, Pokrovskaya City Hospital, St Petersburg; M. Boyarkin,
R. Moiseeva, Aleksandrovskaya City Hospital, St Petersburg; A. Philippov, N. Ryzhman, Military Medical
Academia n.a. S.M. Kirov, St Petersburg; D. Zverev,
N. Bessonova, Maksimilianovskaya City Hospital No.
28, St Petersburg; D. Zateyschikov, L. Minushkina, Federal State Institution, Moscow; N. Gratsiansky, I.
Trifonov, Research Institute of Physical and Chemical Medicine of Federal Agency Healthcare and Social Development, Moscow; V. Zadionchenko, G. Shehyan, State Healthcare Institution of Moscow (Hospital
No. 11), Moscow; V. Lusov, I. Gordeev, Russian State
Medical Universtiy of Federal Agency for Healthcare
and Social Development, Moscow; S. Dobrodeev, I.
Tkachuk, City Hospital No. 28 of Moscow District,
Nizhny Novgorod.
South Africa (296 patients): National lead investigator: A. Dalby. J. Badenhorst, P. Blomerus, Unitas Hospital, Centurion; J. Bayat, S. George, Addington Hospital, Durban; J. Bennett, N. Swanepoel, Wilgers
Hospital, Pretoria; E. Brice, N. van Schaik, Tygerberg
Hospital, Cape Town; P. Commerford, C. Hansa,
Groote Schuur Hospital, Cape Town; A. Dalby, C.
Schamroth, Milpark Hospital, Johannesburg; D. Duncan, C. Stark, East London Private Hospital, East London; R. Dyer, S. Singh, Entabeni Hospital, Durban; A.
Horak, E. Lloyd, Vincent Pallotti Hospital, Cape Town;
A. Jacovides, S. Bedhesi, Midrand Medical Centre, Johannesburg; E. Klug, F. Hellig, Sunninghill Hospital,
Johannesburg; P. Manga, L. Bushidi, Johannesburg
General Hospital, Johannesburg; M. Basson, A. Briel,
Karl Bremer Hospital, Bellville; D. Naidoo, K. Shein, Inkosi Albert Luthuli Central Hospital, Durban; R. Naidu,
R. Pillay, Chatsmed Hospital, Durban; B. Posen, A. van
den Berg, N1 City Hospital, Cape Town; N. Ranjith,
A. Murally, R. K. Khan Hospital, Durban; R. Routier,
H. Wittmer, Olivedale Hospital, Johannesburg; R.
Moodley, M. Govender, Umhlanga Hospital, Durban; H. Theron, N. van der Merwe, Universitas Hospital, Bloemfontein; H. Wellmann, G. Ellis, Helderberg Clinical Trial Centre, Cape Town; C. Zambakides,
T. Venter, Union Hospital, Johannesburg; A.
Koopowitz, St Dominics Hospital, East London; M. Baig,
A. Da Silva, Dr George Mukhari Hospital, GaRankuwa; M. Essop, T. Nunkoo, Chris Hani Baragwanath Hospital, Diepkloof; M. Sarvan, C. Jeena, Victoria Medical Centre, Tongaat.
Spain (290 patients): National lead investigator: J.
Lopez-Sendon. C. Garcia-Garcia, L. Recasens, Hospital del Mar, Barcelona; M. Paz, J. Sevilla, Hospital
Figueres, Figueres (Girona); N. Alonso, C. PascualCarbonell, Hospital Princesa Sophia, Leon; J.
Mayordomo, J. Garcia, Hospital Central de Asturias,
Oviedo; V. Lopez, R. Calvo, Hospital Virgen Macarena,
Sevilla; F. Gonzalez-Vilchez, J. Vazquez, Hospital
Marques Valdecilla, Santander; J. Martinez-Tur, J.
Segui-Chueca, Hospital Can Misses, Eivissa, Islas
Baleares; F. Calvo, O. Diaz, Hospital Meixoeiro de Vigo,
Vigo; J. Guiterrez, A. Jimenez, Hospital Arquitecto Marcide, El Ferrol; P. Marco, F. Zubia, Hospital Ntra. Sa
de Aranzazu, San Sebastian; M. Valdes, F. Pastor, Hos-
©2007 American Medical Association. All rights reserved.
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pital Virgen de la Arrixaca, Murcia; J. GonzalezJuanatey, L. Grigorian, Hospital U. Clinico de Santiago, Santiago de Compostela; P. Ancillo, J. Cortina,
Hospital General de Segovia, Segovia; I. Roldan, P.
Lopez, Hospital Universitario La Paz, Madrid; R. Peraira,
A. Garcia, Hospital Carlos III, Madrid; V. Bertomeu, J.
Quiles, Hospital San Juan, San Juan de Alicante; A.
Martinez-Rubio, A. Aguilar, Corporacion Parc Tauli,
Sabadell (Barcelona); J. Blanco, H. Fornieles, Hospital
Torrecardenas, Almeria; P. Martinez-Romero, Hospital Puerto Real, Puerto Real (Cadiz); R. Rubio, M.
Juarez, Hospital Gregorio Marañon, Madrid; F. Torres,
C. Corona-Siles, Hospital Costa del Sol, Marbella; J.
Balaguer, R. Arroyo, Hospital de Guadalajara, Guadalajara; J. Figueras, C. Pajuelo, Hospital Valle de Hebron, Barcelona; A. Fernandez-Ortiz, C. Maldonado,
Hospital Clinico de Madrid, Madrid; E. de Teresa, M.
Jimenez, Hospital Virgen de la Victoria, Malaga; J.
Cambronero, A. Sanz, Hospital Principe de Asturias,
Madrid; A. Bethencourt, G. Melis, Hospital Son Dureta, Palma de Mallorca; N. Murga, G. Bastos, Hospital de Basurto, Bilbao; M. Pique, B. Balsera, Hospital Arnau de Vilanova, Lerida; J. Martin-Miranda, M.
Ramos, Hospital Candelaria, Santa Cruz de Tenerife;
G. Casares, V. Blanco, Hospital San Agustin, Aviles; J.
Blanco, R. Fajardo, Hospital Virgen del Mar, Almeria;
L. Lopez-Bescos, A. Huelmos, Hospital Alcorcon,
Madrid; M. Heras, M. Puig, Hospital Clinico i Provincial, Barcelona.
United Kingdon (297 patients): National lead investigator: R. Wilcox. A. Moriarty, A. Mackin, Craigavon
Area Hospital, Craigavon; I. Hudson, K. Fairbrother,
Glenfield Hospital, Leicester; H. Kadr, D. Sutton,
Queens Hospital, Romford; A. Pell, J. Anderson,
Monklands Hospital, Airdrie; S. Saltissi, E. DiStefano,
Royal Liverpool University Hospital, Liverpool; M. Pitt,
J. Hulse, Birmingham Heartlands Hospital, Birmingham; E. Hughes, C. Phillips, Sandwell General Hospital, Birmingham; S. Lindsay, L. Akeroyd, Bradford Royal
Infirmary, Bradford; D. Bruce, K. Knops, Poole Hospital, Poole; A. Jacob, P. White, St John’s Hospital, Livingston; C. Francis, V. Bryson, Victoria Hospital, Kirkcaldy; B. O’Rourke, J. Young, Hairmyres District General
Hospital, East Kilbride; P. MacIntyre, J. Dougal, Royal
Alexandra Hospital, Paisley; A. Flapan, S. Speirs, Royal
Infirmary of Edinburgh, Edinburgh; R. Mansfield, M.
Wicks, Royal United Hospital, Bath; N. Qureshi, S. Day,
Warwick Hospital, Warwick; C. Lawson, J. Highland,
Kent & Sussex Hospital, Tunbridge Wells; J. Walsh,
M. Harrison, Queen’s Medical Centre, Nottingham;
R. Robson, A. Graham, Cumberland Infirmary, Carlisle; R. Andrews, J. Wiseman, Lincoln County Hospital, Lincoln; J. Cleland, D. Fellowes, Hull Royal Infirmary, Hull; R. Grocott-Mason, S. McDonagh,
Hillingdon Hospital, Uxbridge; J. Dhawan, J. John,
Scunthorpe General Hospital, Scunthorpe; S. Osula,
K. Randles, Halton General Hospital, Runcorn; D.
Dutka, S. Blackwood, Addenbrooke’s Hospital, Cambridge; R. Bain, I. Rushmer, The Diana Princess of Wales
Hospital, Grimsby; O. Odemuyiwa, J. Arkell, Epsom
General Hospital, Epsom; P. Lewis, J. Curtis, Stepping Hill Hospital, Stockport; A. Jones, J. Brown, Sal-
isbury District Hospital, Salisbury; A. Rozkovec; N. Lakeman, Royal Bournemouth Hospital, Bournemouth; J.
Kooner, N. Ahmed, Ealing Hospital, Southall; S. Kahn,
S. Clayton, Royal Preston Hospital, Preston; M. Pye,
L. Wright, York District Hospital, York; I. Squire, L.
Shipley, Leicester Royal Infirmary, Leicester; J. Murphy, G. Brennan, Darlington Memorial Hospital, Darlington; A. Adgey, P. McAllister, Royal Victoria Hospital, Belfast; R. Wray, H. Pepper, Conquest Hospital,
Hastings; P. Stubbs, C. Steer, Mayday University Hospital, Croydon; R. Henderson, D. Falcon-Lang, Nottingham City Hospital, Nottingham; D. Rowlands, S.
Hamill, Peterborough District Hospital, Peterborough; J. Rowley, C. Roe, Kings Mill Hospital, SuttonIn-Ashfield; I. Haq, C. Albers, Royal Victoria Infirmary, Newcastle-upon-Tyne; Y. Wong, S. Moore, St
Richard’s Hospital, Chichester.
United States (720 patients): National lead investigators: D. Morrow and B. Scirica. A. Virmani, L. Schutz,
Winchester Medical Centre, Winchester, Va; W. Rogers, D. Smith, University of Alabama at Birmingham,
Birmingham; D. Gordon, J. Gehrke, Iowa Heart
Center, Des Moines; Y. Aude, R. Babbitt, University
of Arkansas Veterans Healthcare, Little Rock; S.
Bakir, J. Richardson, Birmingham Baptist Medical
Center−Montclair Hospital, Birmingham, Ala; H. Colfer,
C. Shaw, North Michigan Hospital, Petoskey; J.
deLemos, K. Pinkston, University of Texas Southwestern Medical Center, Dallas; T. Hack, A. Brooks, Primary Care Cardiology Research, Ayer, Mass; S. Wiviott,
A. Gauthier, Brigham and Women’s Hospital, Boston, Mass; C. Kimmelstiel, P. Field, Tufts New England Medical Center, Boston, Mass; S. Rezkalla, K.
Maasen, St Joseph’s Hospital, Marshfield, Wis; B. Clemson, R. Klundt, Heartcare Midwest, Peoria, Ill; M. Koren,
M. Parks, Memorial Hospital Jacksonville/Clinical Research Center, Jacksonville, Fla; K. Aggarwal, A.
Sieckman, University of Missouri, Columbia; G.
Giugliano, R. Giard, Baystate Medical Center, Springfield, Mass; K. Atassi, L. Christy, Porter Memorial Hospital, Valparaiso, Ind; C. Treasure, C. Bales, Cardiovascular Research Foundation, Knoxville, Tenn; R.
Vicari, B. Wallinger, Holmes Regional Medical Center, Melbourne, Fla; G. Langevin, E. Hand, Freeman
Hospital, Joplin, Mo; J. Corbelli, B. Cooke, Buffalo Cardiology & Pulmonary Associates, Williamsville, NY; P.
Hermany, S. Alison, Grandview Hospital, Sellersville,
Pa; J. Mann, T. Doyle, Wake Heart Research LLD, Raleigh, NC; M. Zenni, A. Johnston, University of Florida
Health Science Center, Jacksonville; T. Lassar, G.
Mlinaric, University Hospitals of Cleveland, Cleveland, Ohio; D. Wohns, J. Bishop, Spectrum Health Hospitals, Grand Rapids, Va; H. Anderson, C. Underwood, University of Texas Medical School, Houston;
J. Kieval, J. Friderich, Florida Cardiovascular Research, Atlantis; S. Mohiuddin, E. Butkus, The Cardiac Center of Creighton University, Omaha, Neb; R.
Hundley, P. Cunningham, Heart Clinic Arkansas, Little
Rock; R. Ostfeld, L. Drago, Montefiore Medical Center, Bronx, NY; C. Gessler, T. Cooley, The Heart Center, PC, Huntsville, Ala; T. Sacchi, D. Biracree, New
York Methodist Hospital, Brooklyn; Y. Aude, R. Babbitt,
©2007 American Medical Association. All rights reserved.
University of Arkansas, Littlerock; J. Anderson, A. Vines,
Integris Baptist Medical Center, Oklahoma City, Okla;
S. Sedlis, E. Anteola, New York Harbor Health Care
System, New york; J. DeLeon, B. George, Winthrop
University Hospital, Mineola, NY; J. Kmetzo, M. Eck,
Doylestown Hospital, Doylestown, Pa; M. Williams,
N. Patterson, East Alabama Medical Center, Opelika;
Y. Chandrashekhar, L. Tetrick, Veterans Administration Medical Center Minneapolis, Minneapolis, Minn;
M. Silver, S. Theideman, Wake Med, Raleigh, NC; R.
Bach, M. Palazzolo, Washington University School of
Medicine, St Louis, Mo; E. Lader, M. Meyer, MidValley Cardiology, Kingston, NY; J. Furda, J. Kaliebe,
CARE Foundation Inc, Wausau, Wis; G. Tilton, K. Sorensen, East Jefferson General Hospital, Metairie, La;
M. Kraemer, J. Wells, Mercy Hospital, Minneapolis,
Minn; P. Ouyang, M. Herr, Johns Hopkins Bayview
Medical, Baltimore, Md; J. Kerstein, A. Gill, Maimonides Medical Center, Brooklyn, NY; M. Amidi, M.
Bell, Veterans Administration Medical Center, Pittsburg, Pa; T. O’Brien, L. Harrell, Medical University of
South Carolina, Charleston, SC; F. McGrew, J. Sparks,
Stern Cardiovascular Center, Memphis, Tenn; L.
Rusterholtz, H. Nepote, St Joseph’s Hospital, Tampa,
Fla; V. Singh, M. Richardson, Bayfront Medical Center, St Petersburg, Fla; M. Bikkina, K. Turnbull, St Joseph’s Regional Medical Center, Paterson, NJ; N. Jamal,
K. Dempsey, United Health Services Hospital Inc/
Wilson, Johnson City, NY; A. Riba, J. Gugudis, Oakwood Hospital and Medical Center, Dearborn, Mich;
S. Promisloff, D. Collette, Hillsboro Cardiology, Hillsboro, Ore; R. Laham, L. Donnell-Fink, Angiogenesis
Research Center, Boston, Mass; S. Broadwater, M.
Edwards, Augusta University Hospital, Augusta, Ga;
D. Drachman, I. McNulty, Massachusetts General Hospital, Boston, Mass; S. Eisenberg, S. Mathewson, St
Joseph’s Hospital of Atlanta, Atlanta, Ga; D. Pollock,
D. Overbeck, The Cardiovascular Research Group, Fairfax, Va; J. Burchenal, D. Erickson, Porter Adventist Hospital, Littleton, Colo; K. Carr, M. Peek, Tri-City Medical Center, Oceanside, Calif; A. Doorey, J. Laucirica,
Christiana Care Health Services, Newark, Del; M. Unks,
J. Blakely, Asheville Cardiology Associates, P.A., Asheville, NC; S. Krauss, L. Heaney, Alaska Heart Institute, Anchorage; M. Burke, H. MacDonald, Abbott
Northwestern Hospital, Minneapolis, Minn; M. Lim,
N. Elmore, St Louis University School of Medicine, St
Louis, Mo; M. Feldman, J. Holubec, University of Texas
Health Science Center, San Antonio; E. Illiadis, S. Cruz,
Cooper Health System, Camden, NJ; C. Grines, S.
Workman, William Beaumont Hospital, Royal Oak,
Mich; J. Blankenship, D. Zimmerman, Geisinger Medical Center, Danville, Pa; A. Jain, S. Welch, Ruby Memorial Hospital, Morgantown, WVa; W. Ballard, A.
Tanner, Cardiology of Georgia, Atlanta; K. Sheikh, T.
Hengerer, Wuesthoff Memorial Hospital, Merritt Island, Fla; T.R. Pacheco, D. Wolford, North Ohio Research, Ltd, Lorain; G. Elsner, D. Richardson, The Care
Group, Indianapolis, Ind; P. Reddy, T. Stapleton, Louisiana State University Health Sciences Center University, Shreveport; P. Chandraratna, Veterans Administration Medical Center, Long Beach, Calif.
(Reprinted) JAMA, April 25, 2007—Vol 297, No. 16
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