NEJM CARDIOVASCULAR DISEASE ARTICLES - Part 9 ppsx

n engl j med

353;18

www.nejm.org november

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dyspnea and cardiac prognosis

1897

patient or identified by the referring physician),
and differences in the variables used for propensi-
ty analysis, such as our inclusion of covariates
based on myocardial-perfusion SPECT that reflect
the percentage of ischemic and scarred myocardi-
um. In addition, experience has demonstrated that
differences in “pretest referral biases” (i.e., differ-
ences in the clinical characteristics of referral pop-
ulations)

24,25

can markedly influence the perceived
prognostic accuracy of clinical variables among
studies. Accordingly, there is a need to assess the
extent to which the prognostic significance of dys-
pnea is influenced by pretest referral bias across
various patient populations.

Our study has a number of limitations. Ventric-
ular function was not assessed in all the patients,
since gated myocardial-perfusion SPECT, required
for its assessment, was not routinely performed
until 1995. We used only a single dichotomous ques-
tion concerning dyspnea, which did not grade the
severity or precipitants of the symptom. By com-
parison, the American Thoracic Society uses a five-
point scale for dyspnea.

26

Paradoxically, this limi-
tation underscores the strength of our data, since
dichotomously evaluated test variables generally
convey less inherent information than variables that
are classified in more strata.

27

Since we only coded
dyspnea among patients without chest pain, we
could not evaluate the potential interaction between
dyspnea and symptoms of chest pain. We also did
not evaluate the reproducibility of the self-reported
symptoms. Historical or testing information regard-
ing lung disease would have been useful. In addition,
since our study patients represent a referral popu-
lation for myocardial-perfusion SPECT, caution
should be exercised in extrapolating our findings

to the general population.
The most important limitation of our study is
that, because dyspnea is closely associated with a
variety of both cardiovascular and noncardiovascu-
lar disorders, it may not have been possible to ac-
count for all of the important resulting interac-
tions. However, given the fact that the association
between dyspnea and the outcome persisted after
extensive assessment of the effect of other factors,
it is an important observation that dyspnea as a pre-
senting symptom in patients undergoing nonin-
vasive testing is associated with an increased risk
of death from any cause and from cardiac causes,
perhaps for other reasons in addition to those com-
monly recognized.
In our population, asymptomatic patients with-
out dyspnea had a rate of adverse events that was
similar to the rate among those with chest pain. Sim-
ilar findings have been noted by Christopher Jones
et al.

18

These observations may be due in part to
the tendency to designate as “asymptomatic” pa-
tients with known or suspected cardiac disease who
have symptoms other than chest pain that have been
noted to be associated with an increased incidence
of adverse events, such as a sense of exhaustion,

28

difficulty in relaxing,

29

depressive symptoms,

30

and
sleeplessness.

31

For instance, in a follow-up of 5053
male college alumni, those responding “frequent-
ly” to the question “how often do you experience ex-
haustion (except after exercise)” had twice the rate
of death from cardiac causes as did other respon-
dents over a 12-year follow-up.

28

Given our findings
regarding dyspnea, these other somatic symptoms
may also deserve further study relative to their prog-
nostic significance in cardiac populations.
Our results indicate that dyspnea is an impor-
tant symptom among patients with suspected and

known coronary artery disease and imply that when
dyspnea is present, the likelihood of death from
cardiac causes and from any cause is increased.
On the basis of our results, it may be appropriate
to include an evaluation of dyspnea in the clinical
assessment of patients referred for cardiac stress
testing. It may also be appropriate to include an
evaluation of dyspnea in future efforts to refine al-
gorithms (such as the Duke Treadmill Score) that
are used to assess the prognosis of coronary artery
disease.

Presented in part at the annual American Heart Association Sci-
entific Sessions, New Orleans, November 7–10, 2004.
Dr. Rozanski reports having received lecture fees from Bristol-
Myers Squibb and Pfizer. Dr. Hachamovitch reports having served as
a consultant to King Pharmaceuticals, Bristol-Myers Squibb Medical
Imaging, and Fujisawa Healthcare and having received lecture fees
from Bristol-Myers Squibb Medical Imaging and Fujisawa Healthcare.
Dr. Germano reports having received lecture fees from Bristol-Myers
Squibb. Dr. Berman reports having received grant support from Bris-
tol-Myers Squibb Medical Imaging and Medtronic and lecture fees
from Fujisawa Healthcare and Bristol-Myers Squibb Medical Imag-
ing. The software used to measure ejection fractions and volumes
is owned by Cedars–Sinai Medical Center, which

r

eceives royalties
from its licensing. A minority portion of those royalties is shared by

Drs. Berman and Germano. Dr. Abidov was a Save-A-Heart Founda-
tion Research Fellow in Cardiac Imaging at the Cedars–Sinai Medi-
cal Center during the data collection and analysis.
We are indebted to the nurse practitioners, nuclear technicians,
members of the Artificial Intelligence in Medicine group, research
coordinators, and follow-up team in the Cardiac Imaging Depart-
ment, Cedars–Sinai Medical Center; to Dr. Xingping Kang for tech-
nical assistance in the preparation and submission of the manu-
script; and to Mrs. Heidi Gransar for statistical assistance.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
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n engl j med

353;18

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3

,

2005

1898

dyspnea and cardiac prognosis

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Copyright © 2005 Massachusetts Medical Society.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
original article
The
new england journal of medicine
n engl j med 353;26 www.nejm.org december 29, 2005
2758
Rescue Angioplasty after Failed Thrombolytic
Therapy for Acute Myocardial Infarction
Anthony H. Gershlick, M.B., B.S., Amanda Stephens-Lloyd, R.N., M.Sc.,
Sarah Hughes, R.N., B.A., Keith R. Abrams, Ph.D., Suzanne E. Stevens, M.Sc.,
Neal G. Uren, M.D., Adam de Belder, M.D., John Davis, M.B., B.S.,
Michael Pitt, M.B., B.S., Adrian Banning, M.D., Andreas Baumbach, M.D.,
Man Fai Shiu, M.D., Peter Schofield, M.D., Keith D. Dawkins, M.D.,
Robert A. Henderson, M.D., Keith G. Oldroyd, M.D., and Robert Wilcox, M.D.,
for the REACT Trial Investigators*
From the Department of Cardiology, Uni-
versity Hospitals of Leicester, Leicester
(A.H.G., A.S L., S.H.); the Departments
of Health Sciences (K.R.A.) and Cardio-
vascular Sciences (S.E.S.), University of
Leicester, Leicester; the Department of
Cardiology, Royal Infirmary Edinburgh,
Edinburgh (N.G.U.); Sussex Cardiac Cen-
tre, Royal Sussex County Hospital, Brigh-
ton (A. de Belder); the Department of
Cardiology, North Staffordshire Hospi-

tal, Stoke-on-Trent (J.D.); the Depart-
ment of Cardiology, Heartlands Hospital,
Birmingham (M.P.); the Department of
Cardiology, John Radcliffe Hospital, Ox-
ford (A. Banning); the Department of
Cardiology, Bristol Royal Infirmary, Bris-
tol (A. Baumbach); the Department of
Cardiology, Walsgrave Hospital, Coven-
try (M.F.S.); the Department of Cardiolo-
gy, Papworth Hospital, Cambridge (P.S.);
Wessex Cardiac Unit, Southampton Gen-
eral Hospital, Southampton (K.D.D.);
Trent Cardiac Centre, Nottingham City
Hospital, Nottingham (R.A.H.); the De-
partment of Cardiology, Western Infir-
mary, Glasgow (K.G.O.); and the Depart-
ment of Cardiovascular Medicine,
Queens Medical Centre, Nottingham
(R.W.) — all in the United Kingdom. Ad-
dress reprint requests to Dr. Gershlick at
the University Hospitals of Leicester,
Groby St., Leicester LE3 9QP, United
Kingdom, or at
*The participants in the Rescue Angio-
plasty versus Conservative Treatment or
Repeat Thrombolysis (REACT) trial are
listed in the Appendix.
N Engl J Med 2005;353:2758-68.
Copyright © 2005 Massachusetts Medical Society.
abstract

background
The appropriate treatment for patients in whom reperfusion fails to occur after
thrombolytic therapy for acute myocardial infarction remains unclear. There are
few data comparing emergency percutaneous coronary intervention (rescue PCI) with
conservative care in such patients, and none comparing rescue PCI with repeated
thrombolysis.
methods
We conducted a multicenter trial in the United Kingdom involving 427 patients with
ST-segment elevation myocardial infarction in whom reperfusion failed to occur
(less than 50 percent ST-segment resolution) within 90 minutes after thrombolytic
treatment. The patients were randomly assigned to repeated thrombolysis (142 pa-
tients), conservative treatment (141 patients), or rescue PCI (144 patients). The pri-
mary end point was a composite of death, reinfarction, stroke, or severe heart
failure within six months.
results
The rate of event-free survival among patients treated with rescue PCI was 84.6
percent, as compared with 70.1 percent among those receiving conservative therapy
and 68.7 percent among those undergoing repeated thrombolysis (overall P = 0.004).
The adjusted hazard ratio for the occurrence of the primary end point for repeated
thrombolysis versus conservative therapy was 1.09 (95 percent confidence interval,
0.71 to 1.67; P = 0.69), as compared with adjusted hazard ratios of 0.43 (95 percent
confidence interval, 0.26 to 0.72; P = 0.001) for rescue PCI versus repeated throm-
bolysis and 0.47 (95 percent confidence interval, 0.28 to 0.79; P = 0.004) for rescue
PCI versus conservative therapy. There were no significant differences in mortality
from all causes. Nonfatal bleeding, mostly at the sheath-insertion site, was more com-
mon with rescue PCI. At six months, 86.2 percent of the rescue-PCI group were free
from revascularization, as compared with 77.6 percent of the conservative-therapy
group and 74.4 percent of the repeated-thrombolysis group (overall P = 0.05).
conclusions
Event-free survival after failed thrombolytic therapy was significantly higher with

rescue PCI than with repeated thrombolysis or conservative treatment. Rescue PCI
should be considered for patients in whom reperfusion fails to occur after throm-
bolytic therapy.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
rescue angioplasty or repeated thrombolysis after failed thrombolytic therapy
n engl j med 353;26 www.nejm.org december 29, 2005
2759
P
atients who have an open infarct-
related artery after acute myocardial infarc-
tion with ST-segment elevation have better
clinical outcomes than patients without an open
artery.
1-4
Although primary percutaneous coronary
intervention (primary PCI) is a proven therapeutic
approach in this setting
5,6
and is used increasingly,
intravenous thrombolysis remains the first-line
therapy in 30 to 70 percent of cases worldwide.
7,8

However, thrombolysis results in a grade 3 flow,
according to the Thrombolysis in Myocardial In-
farction (TIMI) classification system, in only 60
percent of patients, even with current fibrin-spe-
cific agents.
9

To date, it has been unclear how best
to treat the remaining patients, in whom throm-
bolysis has failed. Some physicians, particularly
those at hospitals without interventional facilities,
treat such patients conservatively.
10
Others believe
that a second dose of a thrombolytic agent may
be beneficial.
11
Many advocate emergency PCI
(rescue PCI) on the basis of small trials that have
suggested a benefit of this intervention.
12,13
The
Rescue Angioplasty versus Conservative Treatment
or Repeat Thrombolysis (REACT) trial was under-
taken to establish which of these three options
achieves the best clinical outcome among patients
in whom thrombolysis has failed.
methods
We conducted a multicenter, randomized, paral-
lel-group trial that was approved by United King-
dom national and local ethics committees and
fulfilled the conditions of the Declaration of Hel-
sinki. The trial was funded by the British Heart
Foundation; Roche Pharmaceuticals provided re-
teplase for repeated thrombolysis (its use was op-
tional for physician investigators). The sponsors
had no role in study design, data collection, or study

analysis or in the writing of this report.
patients
Between December 1999 and March 2004, trial
candidates were evaluated at 35 centers (which
joined the study on a rolling basis over three years);
19 of the centers had on-site angiographic facilities.
Adults 21 to 85 years of age were eligible for in-
clusion if they had received any licensed throm-
bolytic agent for myocardial infarction with ST-
segment elevation within 6 hours of the onset of
chest pain and if reperfusion had then failed to
occur, as judged by the predetermined 90-minute
electrocardiographic criterion (less than 50 per-
cent resolution in the lead with previous maximal
ST-segment elevation). The inclusion and exclusion
criteria are listed in Table 1. A screening log of
potential subjects was kept through November
2002 to catalogue patients who did or did not par-
ticipate in the trial; however, this log was not
maintained after November 2002 because of fund-
ing constraints. The trial subjects were enrolled
after giving written informed consent.
randomization
Patients were randomly assigned by a 24-hour
computer-generated random-allocation system to
undergo repeated thrombolysis, conservative treat-
ment, or rescue PCI. Patients assigned to repeated
thrombolysis received a fibrin-specific thrombo-
lytic agent (alteplase or reteplase, according to the
physician’s choice) and intravenous heparin, ac-

cording to standard clinical practice. Low-molec-
ular-weight heparin was not used in the first 24
hours. Patients assigned to the conservative-ther-
apy group received standard medical therapy for
myocardial infarction without thrombolysis or PCI.
To ensure a standardized group, conservative ther-
apy included intravenous heparin for 24 hours,
irrespective of the first thrombolytic agent. Hepa-
rin administration in the repeated-thrombolysis
and conservative-therapy groups was titrated to an
activated partial-thromboplastin time ratio of 1.5
to 2.5. Patients assigned to rescue PCI under-
went coronary angiography, proceeding to an-
gioplasty if required (i.e., if the patient had less
than TIMI grade 3 flow and more than 50 percent
stenosis in the infarct-related artery). Adjunctive
strategies (e.g., stenting or glycoprotein IIb/IIIa
receptor inhibition) were used at the discretion
of the interventionist. Crossover among the three
treatment groups was discouraged but was al-
lowed if a patient had ongoing or further chest
pain associated with ST-segment re-elevation or
new elevation in at least two contiguous leads or
had cardiogenic shock.
data collection
Clinical examination, electrocardiography, hema-
tologic measurements, and biochemical tests (in-
cluding measurement of cardiac biomarkers) were
performed on all patients 4 hours after the initia-
tion of the randomly assigned therapy (to account

for the potential time delay to rescue PCI), at 12
and 24 hours after randomization, and at dis-
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
The new england journal of medicine
n engl j med 353;26 www.nejm.org december 29, 2005
2760
Table 1. Criteria for Inclusion and Exclusion and Definitions of Trial End Points.
Inclusion criteria
Acute myocardial infarction with ST-segment elevation of more than 0.1 mV in at least two contiguous leads, excluding V
1
Aspirin and thrombolysis administered within 6 hours of onset of symptoms
Age 21 to 85 years
Ability to give informed consent
At 90 minutes (±15 minutes) after the beginning of initial thrombolytic therapy, electrocardiogram shows failed thrombolytic therapy — i.e.,
less than 50% resolution of the ST segment in the lead showing the greatest ST-segment elevation measured from the baseline (isoelec-
tric line) to 80 msec beyond the J point, with or without chest pain
Rescue angioplasty, if assigned, can be performed within 12 hours of the onset of pain
Exclusion criteria
Probable inability to gain femoral access for intervention (e.g., severe peripheral vascular disease)
Left bundle-branch block
Life expectancy less than 6 months owing to noncardiac cause
Previous inclusion in this trial at any time, or in any other clinical trial during the previous month
Contraindication to thrombolysis (e.g., cardiopulmonary resuscitation after first thrombolytic treatment)
Hemoglobin greater than 1.5 g/dl below normal range within previous 6 hours
Platelet count below normal range within previous 6 hours
For patients 75 years of age or older: systolic blood pressure above 200 mm Hg, diastolic blood pressure above 100 mm Hg, or both at any
time during the current episode of pain, even if successfully reduced by therapy
For patients less than 75 years of age: after prescription of first thrombolytic therapy, systolic blood pressure above 200 mm Hg, diastolic
blood pressure above 100 mm Hg, or both on more than one occasion

Estimated body weight less than 65 kg
Cardiogenic shock, either in the opinion of the investigator or defined as persistent (lasting more than 30 minutes) systolic hypotension (less
than 90 mm Hg) with oliguria and autonomic activation, with or without pulmonary edema despite appropriate volume replacement, and
considered to be due to ventricular dysfunction rather than to any other cause
Administration of low-molecular-weight heparin within the previous 12 hours
Definitions of trial end points
Reinfarction
During index admission: further chest pain lasting more than 30 minutes and accompanied by new electrocardiographic changes (new
Q waves above 0.04 second or ST-segment elevation above 0.1 mV in two leads for more than 30 minutes), further enzyme rise,
or both
Late chest pain lasting more than 30 minutes and accompanied by new electrocardiographic changes, enzyme rise, or both
Cerebrovascular event
A new focal neurologic deficit of presumed vascular cause persisting for more than 24 hours and without evidence of a nonvascular cause
according to a neurologic imaging study
Severe heart failure
Early heart failure: any new-onset cardiogenic shock or heart failure with pulmonary edema that is resistant to medical therapy and that
occurs during the index admission and after randomization
Late heart failure: admission to hospital for treatment of heart failure (New York Heart Association class III or IV)
Bleeding
Major bleeding: decrease in hemoglobin of at least 5 g/dl during index admission, severe bleeding event (e.g., intracranial hemorrhage,
hemopericardium, or hemodynamic compromise, with or without transfusion), or both
Minor bleeding: observed bleeding during index admission, with or without a decrease in hemoglobin of at least 5 g/dl, with or without
transfusion
Blood loss with no identified site: a decrease in hemoglobin of 2 to 4.9 g/dl, or the need for transfusion, without an identified bleeding
site

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rescue angioplasty or repeated thrombolysis after failed thrombolytic therapy
n engl j med 353;26 www.nejm.org december 29, 2005

2761
charge, with clinical follow-up at 1, 6, and 12
months. The components of the primary end
point were continuously documented. More than
90 percent of study data were subjected to source
validation according to strictly controlled cri-
teria.
end points
The primary end point was a composite of major
adverse cardiac and cerebrovascular events at six
months, including death, recurrent myocardial in-
farction, cerebrovascular event, and severe heart
failure. The secondary end points included the
components of the primary end point, as well as
bleeding and revascularization. Events were adju-
dicated by an independent end-point committee,
whose members were blinded to treatment assign-
ment. Quality-of-life and resource-use data were
collected at follow-up. Definitions of all end points
are given in Table 1.
power and sample size
On the basis of the limited evidence available at
the time of study design (1998),
12
the steering
committee estimated that the rate of the primary
composite end point in the conservative-therapy
group would approach 20 percent and hypothe-
sized a 40 percent relative reduction in this rate
in the rescue-PCI group; thus, it was calculated

that 1200 patients would be required (80 percent
power, α = 0.05). In December 2001, the members
of the steering committee and the data and safety
monitoring committee (who did not have access
to the trial data) examined new published evi-
dence suggesting that the rate of death or recur-
rent myocardial infarction would be 29 percent
with conservative therapy, 26.5 percent with re-
peated thrombolysis, and 15 percent with rescue
PCI.
11,13-15
Because the rates of heart failure and
cerebrovascular events were inconsistently report-
ed in those studies, the power of our study was re-
calculated on the basis of assumed rates of death
and recurrent myocardial infarction alone. It was
determined that a sample size of 156 patients in
each group would provide 80 percent power
(α = 0.05) to detect the same 40 percent relative re-
duction in the composite end point that was pre-
viously hypothesized. It was assumed that heart
failure and cerebrovascular events would be likely
to increase rather than reduce such power in the
final analysis.
During 2003 and 2004, enrollment in the trial
began to decline. The precise reason for this de-
cline is uncertain, because the screening log was
not maintained after November 2002 (as noted
above). However, other ongoing clinical trials, as
well as the introduction of the new thrombolytic

agent tenecteplase (and the concomitant unli-
censed use of low-molecular-weight heparin), lim-
ited the number of suitable candidates for partici-
pation. Because of declining trial recruitment and
a finite funding period, the steering committee
terminated enrollment in the trial in March 2004.
statistical analysis
All analyses were performed on an intention-to-
treat basis. Process times are reported as medi-
ans with interquartile ranges and compared with
use of the Kruskal–Wallis test. The proportions of
subjects in each of the groups who reached any
end point during the six months were compared
with use of either the chi-square test or Fisher’s
exact test, as appropriate. Survival and event-free
survival were plotted as Kaplan–Meier curves, and
the log-rank test was used to compare them. Haz-
ard ratios with 95 percent confidence intervals
were calculated for all pairwise comparisons. Cox
proportional-hazards regression models were used
to investigate the potential influence of all base-
line covariates on treatment effects. Covariates
were selected for a final model by a forward vari-
able-selection procedure. The assumption of pro-
portional hazards was assessed both graphically,
with the use of log–log survivor plots, and by
adding associated time-dependent covariates to
the model.
16
There was no evidence that the as-

sumption of proportional hazards was violated in
any of the results presented here. No formal ad-
justment for multiple testing was undertaken, but
the P values were interpreted cautiously. All statis-
tical analyses were performed with SAS software,
version 8.2 (SAS Institute).
results
At the termination of the trial, 435 patients had
been enrolled and randomly assigned to one of the
three treatment groups. Of these, six withdrew
consent (one each in the groups assigned to re-
peated thrombolysis and rescue PCI and four in
the group assigned to conservative therapy), and
another two were excluded (one each in the re-
peated-thrombolysis and rescue-PCI groups) be-
cause they had inappropriately undergone random-
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The new england journal of medicine
n engl j med 353;26 www.nejm.org december 29, 2005
2762
ization before giving consent, which they declined
to do. The data for 427 patients are therefore pre-
sented. Of these, 142 were assigned to repeated
thrombolysis, 141 to conservative therapy, and 144
to rescue PCI (Table 2).
The trial screening log, which was maintained
until November 2002, included 713 patients who
did not undergo randomization (as compared with
304 patients who had undergone randomization

by that date). Of those who did not undergo ran-
domization, most were excluded on the basis of
clinical criteria, including delayed presentation
(beyond six hours) (24 percent), advanced age (21.4
percent), and severe hypertension (13.6 percent).
Only 4.2 percent were excluded on the basis of the
judgment of the patient’s physician.
baseline characteristics
The baseline characteristics were similar in all
groups (Table 2). There was no difference among
the groups in the median time from the onset of
pain to the first (nontrial) thrombolytic treatment
(P = 0.73). The median time from presentation
until the first thrombolytic treatment (“door-to-
needle time”) was 27 minutes (interquartile range,
16 to 43).
Table 2. Baseline Characteristics of Enrolled Patients.
Characteristic Treatment Group
All Patients
(N=427)
Repeated
Thrombolysis
(N=142)
Conservative
Therapy
(N=141)
Rescue PCI
(N=144)
Age — yr
Mean ±SD 61.3 ± 10.3 61.0 ± 10.7 61.1 ± 11.9 61.1 ± 11.0

Range 40–85 37–85 34–85 34–85
Male sex — no. (%) 114 (80.3) 111 (78.7) 113 (78.5) 338 (79.2)
Medical history — no. (%)
Angina 32 (22.5) 29 (20.6) 32 (22.2) 93 (21.8)
Acute myocardial infarction 23 (16.2) 17 (12.1) 14 (9.8)* 54 (12.7)*
Percutaneous coronary inter-
vention
6 (4.2) 4 (2.8) 6 (4.2) 16 (3.7)
Coronary-artery bypass grafting 7 (4.9) 4 (2.8) 7 (4.9) 18 (4.2)
Diabetes 23 (16.2) 16 (11.3) 21 (14.6) 60 (14.1)
Hypertension 60 (42.3) 53 (37.6) 47 (32.6) 160 (37.5)
Smoking history — no. (%)
Currently smoking 70 (49.6)* 65 (46.1) 68 (47.2) 203 (47.7)*
Formerly smoked 41 (29.1)* 42 (29.8) 40 (27.8) 123 (28.9)*
Never smoked 30 (21.3)* 34 (24.1) 36 (25.0) 100 (23.5)*
Anterior infarct — no. (%) 54 (38.0) 66 (46.8) 61 (42.7)* 181 (42.5)*
First thrombolytic therapy —
no. (%)
Reteplase 43 (30.3) 28 (19.9) 42 (29.2) 113 (26.5)
Streptokinase 82 (57.7) 88 (62.4) 84 (58.3) 254 (59.5)
Tenecteplase 2 (1.4) 5 (3.5) 3 (2.1) 10 (2.3)
Tissue plasminogen activator 15 (10.6) 20 (14.2) 15 (10.4) 50 (11.7)
Time to first thrombolytic
therapy (min)
Median 135 150 140 140
Interquartile range 94–217 100–210 95–240 95–220
* Data were missing for one patient.
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rescue angioplasty or repeated thrombolysis after failed thrombolytic therapy

n engl j med 353;26 www.nejm.org december 29, 2005
2763
actual treatment received
Eighteen patients (4.2 percent) did not receive their
randomly assigned treatment. Among the patients
who were assigned to rescue PCI, 14 received con-
servative therapy and 2 received repeated throm-
bolysis; among the patients who were assigned
to repeated thrombolysis, 1 received conservative
therapy and 1 received rescue PCI. The results of
the analysis according to the intention-to-treat
principle were unchanged when the data were
analyzed according to actual treatment received.
rescue pci
Of the 144 patients assigned to rescue PCI, 88
(61.1 percent) were recruited from hospitals with
interventional capabilities. The median transfer
time for patients from hospitals without interven-
tional capabilities was 85 minutes (interquartile
range, 55 to 120). Sixteen patients in this group
crossed from their assigned therapy, and 128 pro-
ceeded to angiography, 13 of whom did not re-
quire angioplasty because of patent vessels. Of
the remaining 115 patients, only 9 were deemed
to have had an unsuccessful rescue-PCI proce-
dure; in 6 of these patients the artery was deemed
not amenable to PCI, in one instance affecting
1 patient there was a technical failure of x-ray
equipment, and in 2 patients the attempts to open
the artery were unsuccessful.

Rescue PCI was commenced (i.e., the wire
crossed the lesion) a median of 414 minutes af-
ter the onset of pain (interquartile range, 350 to
505). Stents were deployed in 68.5 percent of pa-
tients, and a glycoprotein IIb/IIIa receptor inhibitor
(abciximab) was administered in 43.4 percent. For
patients assigned to rescue PCI rather than re-
Table 3. End-Point Events Occurring within Six Months of Treatment.*
End Point Treatment Overall P Value
Repeated
Thrombolysis
(N = 142)
Conservative
Therapy
(N = 141)
Rescue PCI
(N = 144)
Primary end-point events (predetermined
hierarchical analysis)
Death from any cause — no. (% of patients) 18 (12.7) 18 (12.8) 9 (6.2) 0.12
Death from cardiac causes — no. (% of pa-
tients)
15 (10.6) 14 (9.9) 8 (5.6) 0.26
Recurrent acute myocardial infarction —
no. (% of patients)
15 (10.6) 12 (8.5) 3 (2.1) <0.01
Cerebrovascular event —
no. (% of patients)
1 (0.7) 1 (0.7) 3 (2.1) 0.63
Severe heart failure — no. (% of patients) 10 (7.0) 11 (7.8) 7 (4.9) 0.58

Composite primary end point —
no. (% of patients)
44 (31.0) 42 (29.8) 22 (15.3) <0.01
Secondary end point
Bleeding events
Major bleed — no. of patients
(no. of deaths)
7 (5) 5 (3) 4 (0) 0.65
Minor bleed — no. of patients (no. sheath-
related)
10 (3) 8 (0) 33 (28) <0.001
Blood loss with no identified site —
no. of patients
34 33 19 0.12
Revascularization
PCI or CABG — no. (% of patients) 33 (23.2) 29 (20.6) 19 (13.2) 0.08†
* PCI denotes percutaneous coronary intervention, and CABG coronary-artery bypass grafting. The proportions of sub-
jects in each of the groups who reached any end point during the six months were compared by either the chi-square
test or Fisher’s exact test, as appropriate.
† P = 0.05 by the log-rank test.
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The new england journal of medicine
n engl j med 353;26 www.nejm.org december 29, 2005
2764
peated thrombolysis, the median additional delay
in the time to the assigned treatment was 84 min-
utes (4.6 hours for rescue PCI vs. 3.2 hours for
repeated thrombolysis).
primary end point

All components of the primary end point were re-
corded for 406 subjects (95.1 percent). Mortality
status was confirmed for the remaining 21 sub-
jects (4.9 percent): 6 each in the repeated-throm-
bolysis and conservative-therapy groups and 9 in
the rescue PCI-group. Data on these subjects were
included in the analyses as censored observations,
with a median study period of 105 days (range,
5 to 177).
In the rescue-PCI group, 15.3 percent of the
patients reached at least one component of the
primary end point, as compared with 31.0 percent
in the repeated-thrombolysis group and 29.8 per-
cent in the conservative-therapy group (overall
P = 0.003) (Table 3). The rate of event-free survival
(Fig. 1) was 84.6 percent in the rescue-PCI group,
as compared with 70.1 percent in the conservative-
therapy group and 68.7 percent in the repeated-
thrombolysis group (overall P = 0.004). Among
patients assigned to rescue PCI, there was no
significant difference in event rates between those
who were transferred for intervention (16.4 per-
cent) and those who were recruited in hospitals
with on-site facilities for intervention (14.6 per-
cent, P = 0.80), and logistic-regression analysis indi-
cated that the time to repeated PCI (up to 12 hours)
had no significant effect on outcome. Although
the numbers are very small, the incidence of the
primary end point was much higher among those
who underwent unsuccessful rescue PCI (5 of

9 patients [55.6 percent]) than among those who
underwent successful rescue PCI (12 of 106 pa-
tients [11.3 percent], P = 0.007).
Age and infarct site were the only baseline char-
acteristics that were identified as predictors of the
primary end point by multivariate analysis. Ad-
justed pairwise hazard ratios (Fig. 2) confirmed a
statistically significant benefit of rescue PCI as
compared with conservative therapy (hazard ra-
tio, 0.47; 95 percent confidence interval, 0.28 to
0.79; P = 0.004) and repeated thrombolysis (haz-
ard ratio, 0.43; 95 percent confidence interval, 0.26
to 0.72; P = 0.001). There was no significant differ-
ence in benefit between repeated thrombolysis
and conservative therapy (hazard ratio, 1.09; 95
percent confidence interval, 0.71 to 1.67; P = 0.69).
components of the primary end point
There was a trend toward lower mortality at six
months in the rescue-PCI group (6.2 percent) than
in either the repeated-thrombolysis group (12.7
percent) or the conservative-therapy group (12.8
percent, P = 0.12 for both comparisons) (Table 3).
When the rescue-PCI group was compared with
the two other groups combined, this difference
was statistically significant (hazard ratio, 0.48;
95 percent confidence interval, 0.23 to 0.99; P<0.05).
Multivariate analysis identified age and diabetes
as significant predictors of death, and the adjusted
hazard ratios significantly favored rescue PCI: the
hazard ratio for rescue PCI as compared with re-

peated thrombolysis was 0.42 (95 percent confi-
dence interval, 0.19 to 0.94; P<0.04), and the hazard
ratio for rescue PCI as compared with conserva-
tive therapy was 0.42 (95 percent confidence in-
terval, 0.19 to 0.94; P<0.04). The trial was not pow-
ered to detect a difference in mortality alone.
There were no significant differences in the
rates of cerebrovascular events or severe heart fail-
ure among the three treatment groups (Table 3).
However, the rate of recurrent myocardial infarc-
tion was significantly lower in the rescue-PCI
group (2.1 percent) than in the repeated-throm-
bolysis group (10.6 percent) or the conservative-
therapy group (8.5 percent); the hazard ratio for
rescue PCI as compared with repeated thromboly-
1.00
Probability of Event-free Survival
0.80
0.90
0.70
0.60
0.00
0 20 40 60 80 100 120 140 160 180
200
Rescue PCI 84.6%
95% CI, 78.7–90.5%
Repeated thrombolysis 68.7%
95% CI, 61.1–76.4%
Conservative therapy 70.1%
95% CI, 62.5–77.7%

Days after Randomization
No. of Event-free Patients
Repeated thrombolysis
Conservative therapy
Rescue PCI
93
93
115
95
95
116
96
96
117
99
97
118
99
98
120
101
99
122
105
102
124
106
104
127
110

109
129
P=0.004
Figure 1. Kaplan–Meier Estimates of the Cumulative Rate of the Composite
Primary End Point (Death, Recurrent Myocardial Infarction, Severe Heart
Failure, or Cerebrovascular Event) within Six Months.
PCI denotes percutaneous coronary intervention, and CI confidence interval.
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rescue angioplasty or repeated thrombolysis after failed thrombolytic therapy
n engl j med 353;26 www.nejm.org december 29, 2005
2765
sis was 0.23 (95 percent confidence interval, 0.09
to 0.62; P = 0.004), and the hazard ratio for rescue
PCI as compared with conservative therapy was
0.33 (95 percent confidence interval, 0.12 to 0.93;
P = 0.04).
bleeding complications
Bleeding events were defined according to a mod-
ified TIMI classification (Table 1).
17
There were no
significant differences among the groups in ma-
jor bleeding events (Table 3). However, there was
a tendency toward higher mortality from major
bleeding episodes in the repeated-thrombolysis
group (four deaths from hemopericardium and
one death from intracranial hemorrhage) and the
conservative-therapy group (one death from he-
mothorax and two deaths from intracranial hem-

orrhage) than in the rescue-PCI group, in which
there were no deaths associated with bleeding
events. Minor bleeding episodes were significantly
more frequent in the rescue-PCI group (P<0.001);
minor bleeding occurred at the access site in 28
patients, 5 of whom required blood transfusion.
Among the patients in the rescue-PCI group who
had bleeding events, 69 percent had received ab-
ciximab, as compared with 43 percent of all pa-
tients in this group (P = 0.17). There were no sig-
nificant differences among the groups in the
incidence of bleeding episodes characterized by
a fall in hemoglobin without an identified bleed-
ing site.
revascularization
Revascularization rates tended to be lower in the
rescue-PCI group (Table 3). At six months, 86.2
percent of the patients in the rescue-PCI group
were free from revascularization, as compared
with 77.6 percent of those undergoing conserva-
tive therapy and 74.4 percent of those undergoing
repeated thrombolysis (overall P = 0.05 by the log-
rank test). The unadjusted hazard ratio for revas-
cularization was 0.50 (95 percent confidence in-
terval, 0.29 to 0.88; P<0.02) for rescue PCI as
compared with repeated thrombolysis and 0.58
(95 percent confidence interval, 0.33 to 1.04;
P<0.07) for rescue PCI as compared with conser-
vative therapy. There was no difference between
the two groups not assigned to rescue PCI (haz-

ard ratio for repeated thrombolysis as compared
with conservative therapy, 1.17; 95 percent confi-
dence interval, 0.71 to 1.92; P = 0.56).
discussion
Our study compared three therapeutic options af-
ter failed thrombolytic therapy. We found that res-
cue PCI was superior to either conservative care
or repeated thrombolysis, even though a substan-
tial proportion of patients treated with rescue PCI
were transferred from hospitals without interven-
tional facilities, and there was a median addition-
al time delay of 84 minutes until treatment with
rescue PCI in comparison with repeated throm-
bolysis. A trend toward a higher frequency of fatal
bleeding was noted in both the conservative-treat-
ment group and the repeated-thrombolysis group,
but given the small number of cases reported, no
firm conclusions can be drawn from these data.
The higher rates of nonfatal bleeding in the res-
cue-PCI group may be due to the use of glycopro-
tein IIb/IIIa receptor inhibitors.
Previous evidence supporting the use of res-
cue PCI is limited, and current guidelines rec-
ommend it only for certain high-risk subgroups
of patients.
18,19
Rescue PCI has been reported to
lower the rate of recurrent myocardial infarction,
reduce the incidence of early severe heart failure,
and improve one-year survival.

12,15
However, the
sample sizes in most studies have been small;
moreover, failed rescue PCI has been associated
with a high incidence of adverse outcomes (ap-
proximately 30 percent),
14,20
a result that could
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
2.0
HR, 1.09
95% CI, 0.7
1–1.67
HR, 0.43
95% CI, 0.2
6–0.72
HR, 0.47
95% CI, 0.2
8–0.79
Hazard Ratio
Repeated thrombolysis (n=142) vs.
conservative treatment (n=141)
Rescue PCI (n=144)
vs. repeated
thrombolysis (n=142)
Rescue PCI (n=144)
vs. conservative
treatment (n=141)
Figure 2. Adjusted Hazard Ratios for the Occurrence of the Composite
Primary End Point (Death, Recurrent Myocardial Infarction, Severe Heart

Failure, or Cerebrovascular Accident) among the Trial Groups.
HR denotes hazard ratio, CI confidence interval, and PCI percutaneous cor-
onary intervention.
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The new england journal of medicine
n engl j med 353;26 www.nejm.org december 29, 2005
2766
reduce the overall benefit of the technique.
21,22

The recent use of stents and glycoprotein IIb/IIIa
receptor inhibitors may have improved outcomes
in comparison with those in studies performed in
the mid-1990s.
The findings of our study favoring the use of
rescue PCI contradict those of the recent Middles-
brough Early Vascularization to Limit Infarction
(MERLIN) trial,
23
which found a significant re-
duction in revascularization rates only. There are
a number of important differences between the
two trials. The MERLIN trial was a locally con-
fined study, whereas ours was a national multi-
center trial. In the MERLIN trial, the first throm-
bolytic agent was more often streptokinase (96
percent, vs. 59 percent in our trial), and eligibility
was determined on the basis of electrocardiogra-
phy at 60 minutes, rather than 90. This strategy

may have reduced the rates of the end points in
the conservative-treatment group, since some pa-
tients treated with streptokinase probably under-
went perfusion at 60 to 90 minutes (as suggested
by the fact that 40 percent of the patients in the
rescue-PCI group had TIMI grade 3 flow ac-
cording to angiography before intervention). The
MERLIN trial also showed lower rates of stent-
ing and of glycoprotein IIb/IIIa inhibitor use,
which may have contributed to a higher reinfarc-
tion rate in the rescue-PCI group. For reasons that
remain unexplained, the mortality in the rescue-
PCI group was unusually high in the MERLIN
trial,
20
as was the rate of cerebrovascular events
in this group (4.6 percent). In addition, despite
the absence of a group randomly assigned to re-
peated thrombolytic treatment, 11.7 percent of the
conservatively treated patients in the MERLIN trial
underwent repeated thrombolysis, further con-
founding the results.
The optimal approach for detecting the fail-
ure of thrombolytic therapy has been the subject
of much debate.
24,25
Historically, entry into studies
of rescue PCI has been determined by angiograph-
ic findings,
13,26

whereas in clinical practice, failure
of reperfusion is generally detected by clinical,
noninvasive markers. There is evidence that the
ratios of biochemical markers (including creatine
kinase MB fraction, troponin, and myoglobin
mass) measured before and 60 minutes after the
administration of thrombolytic therapy have good
predictive value,
27,28
with low ratios correlating
with poor patency. However, differential degrees
of ST-segment resolution also correlate well with
TIMI flow grade
29-31
and predict longer-term out-
come.
32
The value of ongoing pain as a sensitive
marker of nonreperfusion is questionable, given
its low specificity
33
and the routine use of analge-
sia. Although certain markers (e.g., myoglobin)
may be considered the most sensitive for detecting
failed thrombolytic therapy, these were not widely
available in the clinical setting when our trial was
designed. Therefore, an ST-segment resolution of
50 percent was considered the most reliable pos-
sible entry criterion, and this cutoff was deemed
likely to pick up most reperfusion failures, with a

low rate of false positives for patent arteries.
30,32,34
Although the trial was terminated early, ter-
mination occurred before the investigators were
unblinded to the data and was necessary, given
the falling recruitment rates and the finite fund-
ing period for the study. In the absence of a full
registry, we cannot exclude some element of selec-
tion bias in the population enrolled. However, all
consecutive patients at each site in whom throm-
bolytic therapy had failed were evaluated, and the
baseline characteristics as recorded in the screen-
ing log until November 2002 do not suggest such
bias. The great majority of patients, according to
this record, were excluded for predefined clinical
reasons, with only 4.2 percent being excluded by
choice of the patient’s physician.
In conclusion, the trial found that rescue PCI
after failed thrombolytic treatment was associated
with a statistically significant reduction in the in-
cidence of major adverse cardiac and cerebrovas-
cular events, as compared with either repeated
thrombolysis or conservative management. These
results indicate that rescue PCI, with transfer to
a tertiary site if required, should be considered for
patients in whom thrombolysis for myocardial in-
farction with ST-segment elevation fails to achieve
reperfusion.
Dr. Gershlick reports having served as a consultant to and re-
ceived lecture fees from Cordis, Boston Scientific, and Medtronic

and being currently in receipt of research grant support from
Medtronic; Dr. Baumbach, having served as a consultant to
Boston Scientific; Dr. Schofield, having served as a consultant to
Cordis and Guidant; and Dr. Dawkins, having served as a consul-
tant to Eli Lilly, Boston Scientific, Guidant, and Conor
Medsystems, having received lecture fees from Eli Lilly, Boston
Scientific, and Guidant, and having appeared as an expert wit-
ness for Boston Scientific. No other potential conflict of interest
relevant to this article was reported.
We are indebted to Leslie Shortt for data entry, and to the
nursing and medical staff of the cardiac care units and catheter
laboratories at all sites.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
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rescue angioplasty or repeated thrombolysis after failed thrombolytic therapy
n engl j med 353;26 www.nejm.org december 29, 2005
2767
appendix
The members of the REACT trial were as follows: Steering Committee — A.H. Gershlick (principal investigator), M. de Belder, H.
Swanton, R. Wilcox, K. Abrams, D. de Bono (deceased), and A. Stephens-Lloyd; Data and Safety Committee — K. Fox, J. Birkhead, and
M. Bland; End-Point Committee — J. Hampton and S. Davies; Trial coordinators — A. Stephens-Lloyd and S. Hughes; Statisticians — S.
Stevens, K. Abrams, and A. Skene; Economic evaluation — M. Buxton and M. Dyer; Investigators, interventionists, and study-site coor-
dinators — Glenfield Hospital, Leicester: J.D. Skehan, J. Kovac, N.J. Samani, and P.J.B. Hubner; Leicester Royal Infirmary, Leicester: I. Squire, L.
Shipley, and E. Parker; Leicester General Hospital, Leicester: I. Hudson, R. Pathmanathan, and K. Fairbrother; Royal Infirmary of Edinburgh, Ed-
inburgh: N.G. Uren, D.E. Newby, P. Bloomfield, N.A. Boon, A.D. Flapan, L. Flint, M. O’Donnell, and L. Cameron; Royal Sussex County
Hospital, Brighton: A. de Belder, S. Holmberg, D. Hildick-Smith, N. Cooter, and L. Bennett; North Staffordshire Hospital, Stoke-on-Trent: J.
Davis, J. Nolan, J. Creamer, D. O’Gorman, J. Machin, and C. Butler; Heartlands Hospital, Birmingham: M. Pitt, P. Ludman, G. Murray, J.
Beattie, S. Eccleshall, N. El-Gaylani, J. Pitt, and J. Hulse; Hull Royal Infirmary, Hull: M. Norell, F. Alamgir, J. Caplin, G. Kaye, A. Clark,
M. Nasir, J. Bristow, A. Fussey, E. Owen, and A. Baksh; John Radcliffe Hospital, Oxford: A. Banning, N. Alp, H. McCullough, N. Meldrum,
C. Hamer, and R. Douthwaite; Bristol Royal Infirmary, Bristol: A. Baumbach, G. Dalton, and K. Carson; Walsgrave Hospital, Coventry: M.F.

Shiu, H. Singh, M. Been, P. Glennon, S. Constantinides, and L. Gill; Hairmyres Hospital, East Kilbride: K. Oldroyd, B.D. Vallance, J. Young,
and G. Moreland; Papworth Hospital, Cambridge: P. Schofield, M.C. Petch, L.M. Shapiro, S.C. Clarke, H. Millington, A. Emerton, and C.
Rhydwen; Southampton General Hospital, Southampton: K. Dawkins, I. Simpson, H. Gray, A. Calver, J. Morgan, Z. Nicholas, and S. Kitt;
Addenbrookes Hospital, Cambridge: P. Weissberg, S. Blackwood; Nottingham City Hospital, Nottingham: R. Henderson, D. Falcon-Lang, and M.
Marriott; University Hospital of Wales, Cardiff: W. Penny and L. Davies; Royal Devon and Exeter Hospital, Exeter: B. Smith, M. Gandhi, J. Dean,
C. Rinaldi, A. Renouf, D. Taylor, and J. Hunt; Royal Surrey County Hospital, Guildford: E. Leatham, R. Mitra, S. Green, and M. Eaton; Wishaw
General Hospital, Wishaw, Larnarkshire: M. Malekian and A. Sloey; Derby Royal Infirmary, Derby: M. Millar-Craig and A. Joy; St. Thomas’ Hospital,
London: S. Redwood, S. Patel, and S. Hogun; Epsom General Hospital, Epsom: S. Odemuyiwa, A. Redwood, and C. Cooper; Southmead Hospi-
tal, Bristol: P. Walker, K. Potts, and D. Foster-Hargreaves; West Suffolk Hospital, Bury-St-Edmunds: E. Lee and S. Reader; Western Infirmary,
Glasgow: K. Oldroyd, S. Robb, W. Hillis, and J. Kelly; Crosshouse Hospital, Kilmarnock: D. O’Neill and O. El-Wassief; Manchester Heart Centre,
Manchester: N. Curzen, F. Fath-Ordoubadi, L. Neyses, and H. Iles-Smith; Royal Alexandra Hospital, Paisley: S. Hood, I. Findlay, and J. Dou-
gall; Hemel Hempstead General Hospital, Hemel Hempstead:
D. Hackett and L. Birkhead; Kent and Sussex Hospital, Tunbridge Wells: C. Lawson and
J. Highland; Middlesex Hospital, London: H. Swanton and E. Firmin; St. Mary’s Hospital, London: R. Foale, J. Mayet, S. Smart, and J. Var-
ghese.
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Castello A, Mauri F. Efficacy of rescue
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Ellis SG, da Silva ER, Heyndrickx G, et
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Parmar MKB, Machin D. Survival
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Antman EM, Anbe DT, Armstrong PW,
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McKendall GR, Forman S, Sopko G,
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EM, et al. Myoglobin, creatine-kinase-MB

and cardiac troponin-I 60-minute ratios
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K, Dissmann R, Meyer-Sabellek W. Extent
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therapy. Circulation 2000;101:2138-43.
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31.
32.
33.
34.
CLINICAL

TRIAL

REGISTRATION
The Journal encourages investigators to register their clinical trials
in a public trials registry. The members of the International Committee
of Medical Journal Editors plan to consider clinical trials for publication
only if they have been registered (see N Engl J Med 2004;351:1250-1).
The National Library of Medicine’s www.clinicaltrials.gov is a free registry,
open to all investigators, that meets the committee’s requirements.
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n engl j med 357;5 www.nejm.org august 2, 2007
PERS P E CTIVE
439
O
nly 30 or 40 years ago,
rheumatic fever was a com-
mon topic in the Journal. A PubMed
search for articles on rheumatic
fever published between 1967 and
1976 returned 55 New England Jour-
nal of Medicine articles — fewer
than for endocarditis (77) but
more than for stroke and syphi-
lis (24 entries each). A similar
PubMed search for the decade
1997 through 2006 yielded just
eight entries for rheumatic fever.
This trend holds for all Medline-
indexed journals: an average of
516 articles on rheumatic fever per

year from 1967 through 1976,
but only 172 per year from 1997
through 2006. Most observers
would probably consider this de-
crease to be a reasonable reflec-
tion of the waning incidence of
the disease. After all, in the mid-
20th century, children with rheu-
matic fever occupied many of the
beds in pediatric wards in indus-
trialized countries — indeed, en-
tire hospitals were dedicated to
the treatment of, and rehabilita-
tion from, rheumatic fever. But
in the latter half of the 20th
century, rheumatic fever receded
as an important health problem
in almost all wealthy countries.
Today, most physicians in these
countries are unlikely ever to see
a case of acute rheumatic fever,
and their experience with rheu-
matic heart disease will be lim-
ited to heart-valve lesions in older
patients who had rheumatic fever
in their youth.
The reality, however, is that the
decrease in publications reflects
only the waning burden of disease
among the less than 20% of the

world’s population living in high-
income countries. For everyone
else, rheumatic fever and rheumat-
ic heart disease are bigger prob-
lems than ever. It was estimated
recently that worldwide 15.6 mil-
lion people have rheumatic heart
disease and that there are 470,000
new cases of rheumatic fever and
233,000 deaths attributable to
rheumatic fever or rheumatic heart
disease each year.
1
These are con-
servative estimates — the actual
figures are likely to be substan-
tially higher. Almost all these cas-
es and deaths occur in developing
countries.
How did rheumatic fever be-
come rare in wealthy countries?
Medical science can take some of
the credit, thanks largely to the
use of penicillin for primary pre-
vention, but most of the reduction
is attributable to improved living
conditions, which have resulted in
less overcrowding and better hy-
giene, with consequent reductions
in transmission of group A strep-

tococci. In other words, rheumatic
fever is a disease of poverty. That
it is in many ways the epitome of
diseases of poverty and social in-
justice is exemplified by the situ-
ations in Australia and New Zea-
land. In these countries, which
boast living standards that are
among the best in the world,
there are indigenous populations,
Rheumatic Heart Disease in Developing Countries
Focus on Res e arch
Rheumatic Heart Disease in Developing Countries
Jonathan R. Carapetis, Ph.D., F.R.A.C.P.
Related article, page 470
an impressive list of unexpected
associations between genes or
chromosomal regions and a broad
range of diseases. There have
been few, if any, similar bursts
of discovery in the history of med-
ical research. Relatively conven-
tional statistical techniques are
adequate for the analysis and in-
terpretation of these initial stud-
ies. But as we delve further into
the genome in the search for net-
works of interacting gene vari-
ants and interactions between
these networks and environmen-

tal factors,
5
much more sophis-
ticated methods of statistical
analysis are likely to be required.
Dr. Hunter is a professor of epidemiology at
the Harvard School of Public Health, Bos-
ton, a statistical consultant to the Journal,
and codirector of the National Cancer In-
stitute’s Cancer Genetic Markers of Sus-
ceptibility project. Dr. Kraft is an assistant
professor of epidemiology and biostatis-
tics at the Harvard School of Public Health,
Boston.
This article (10.1056/NEJMp078120) was
published at www.nejm.org on July 18, 2007.
Christensen K, Murray JC. What genome-
wide association studies can do for medi-
cine. N Engl J Med 2007;356:1094-7.
Witte JS. Multiple prostate cancer risk vari-
ants on 8q24. Nat Genet 2007;39:579-80.
Wacholder S, Chanock S, Garcia-Closas
M, El Ghormli L, Rothman N. Assessing the
probability that a positive report is false: an
approach for molecular epidemiology stud-
ies. J Natl Cancer Inst 2004;96:434-42.
NCI-NHGRI Working Group on Replica-
tion in Association Studies, Chanock S, Mani-
olo T, et al. Replicating genotype-phenotype
associations. Nature 2007;447:655-60.

Thomas DC, Clayton DG. Betting odds
and genetic associations. J Natl Cancer Inst
2004;96:421-3.
Copyright © 2007 Massachusetts Medical Society.
1.
2.
3.
4.
5.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
PERS P E CTIVE
n engl j med 357;5 www.nejm.org august 2, 2007
440
many of whose members live in
poverty, with documented rates
of rheumatic fever and rheumat-
ic heart disease that are among
the highest in the world.
1
Among
aboriginal people of northern Aus-
tralia, for example, acute rheu-
matic fever develops in 0.2 to
0.5% of school-age children each
year, and more than 2% of peo-
ple of all ages have rheumatic
heart disease.
An unfortunate consequence
of the decline in rheumatic fever

in industrialized countries has
been a parallel reduction in re-
lated research. Indeed, although
our understanding of the patho-
genesis of this mysterious dis-
ease has improved somewhat, the
only advances that have substan-
tially altered the management or
prevention of rheumatic fever dur-
ing the past 40 or 50 years have
occurred in the medical and sur-
gical treatment of severe rheu-
matic heart disease — treatment
that is largely palliative and nei-
ther accessible nor affordable to
the majority of affected patients.
The mainstays of the control of
rheumatic fever remain treatment
of group A streptococcal pharyn-
gitis with penicillin (primary pro-
phylaxis) and administration of
penicillin G benzathine injections
every 3 to 4 weeks for many years
in people with a history of rheu-
matic fever to prevent recurrent
episodes (secondary prophylaxis).
Both strategies are based on find-
ings from seminal studies in the
United States published in the
1950s.

2,3
The available and potential con-
trol measures for rheumatic fe-
ver and rheumatic heart disease
are summarized in the diagram.
Of these, only one — secondary
prophylaxis — has been proved
to be cost-effective and practical
even in the poorest countries. For
more than 20 years, the World
Health Organization has recom-
mended secondary prophylaxis,
most effectively delivered within
a coordinated program using a
registry of patients, as the first
priority for the control of rheu-
matic heart disease.
4
Yet most
developing countries still do not
have effective secondary-prophy-
laxis programs.
How to ensure that secondary
prophylaxis is delivered to those
who need it is one of several crit-
ical questions related to the imple-
mentation of current knowledge
about the control of rheumatic fe-
ver and rheumatic heart disease.
Other relevant questions include

how to identify people with mild
rheumatic heart disease so that
they may be offered secondary
prophylaxis earlier, whether pri-
mary prophylaxis can be a practi-
cal and cost-effective public health
measure in developing countries,
and how to ensure that limited
health care funds are spent most
effectively — which may entail
shifting some funding from the
provision of expensive cardiac sur-
gery for severe rheumatic heart
disease to the development of ro-
bust secondary-prophylaxis pro-
grams.
Other key issues revolve around
the need to develop new approach-
es to primary prevention, partic-
ularly a vaccine that protects
against rheumatic fever. A num-
ber of vaccines are in development,
and a safe and effective vaccine
may well be available within one
or two decades. However, experi-
ence with other relatively recent
vaccines, including conjugate
pneumococcal and Haemophilus in-
fluenzae type B vaccines, suggests
that there may be many barriers

to the funding, acceptance, and
use of new vaccines in the places
that need them most. Potential
alternative strategies, including
controlling streptococcal skin in-
fections, are intriguing but of un-
proven benefit.
5
How will these issues be ad-
Rheumatic Heart Disease in Developing Countries
33p9
Rheumatic heart disease
Acute rheumatic fever
Group A streptococcal infection
Causal Pathway Preventive Measures
Cardiac
failure
Stroke,
endocarditis
Death
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
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ICM
CASE
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AUTHOR, PLEASE NOTE:
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REG F
Enon
1st
2nd
3rd
Carapetis
1 of 1
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ARTIST: ts
35705
“Primordial” prevention
Housing
Hygiene
Primary prevention
Sore-throat treatment
Vaccine (unavailable)
Control of skin infections
(unproved)
Secondary prevention
Secondary prophylaxis
“Tertiary” prevention
Medication for heart failure
Valve surgery

Anticoagulation
Potential Preventive Measures for Rheumatic Fever and Rheumatic Heart Disease.
“Sore-throat treatment” refers to primary prophylaxis — that is, diagnosis and treat-
ment of group A streptococcal pharyngitis.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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n engl j med 357;5 www.nejm.org august 2, 2007
PERS P E CTIVE
441
dressed? Although some basic re-
search on pathogenesis and the
development of early-stage vac-
cine candidates can take place in
laboratories anywhere in the
world, the clinical, epidemiolog-
ic, and public health studies re-
quire access to populations with
high rates of disease. In recent
years, many such studies have been
conducted in Australia, New Zea-
land, and the Rocky Mountain
region of the United States. But
applied research of relevance to
developing countries should take
place in developing countries —
a proposition that presents many
obvious challenges. Even if bar-
riers caused by poor education,
the absence of a skilled work-
force, limited finances, inadequate

technology, and remoteness of the
populations that are at the high-
est risk of disease can be over-
come, the burden of rheumatic
fever and rheumatic heart disease
is often either unappreciated or
dwarfed by epidemics of human
immunodeficiency virus, malaria,
tuberculosis, and pneumonia.
Marijon and colleagues are to
be applauded for the results of the
study reported in this issue of
the Journal (pages 470–476). The
study represents a partnership
among researchers in Mozam-
bique, Cambodia, France, and
Australia. It tackles an important
practical issue: whether and how
to conduct screening for rheumat-
ic heart disease among school-age
children in developing countries.
Also, it presents a compelling ar-
gument for the use of echocar-
diographic screening (see image).
The counterargument is that the
use of such expensive technology
is neither feasible nor affordable
in the countries with the highest
disease burden. Yet if clinical di-
agnosis had been relied on, ap-

proximately 90% of echocardio-
graphically detected cases would
have been missed. It is not ac-
ceptable to leave these cases un-
diagnosed and these children at
risk for recurrence of rheumatic
fever simply because echocardio-
graphic screening is seen as an
inappropriate use of modern tech-
nology in developing countries.
Instead, further research is need-
ed to define models of echocar-
diographic screening that are
practical, affordable, and widely
applicable.
Marijon et al. found that 2 to
3% of school-age children in
Cambodia and Mozambique have
rheumatic heart disease, almost
all of it previously undiagnosed.
We know that this represents the
tip of the iceberg: cases in chil-
dren 5 to 14 years of age are like-
ly to represent only 15 to 20% of
all cases in the population.
1
These
data confirm that rheumatic fe-
ver and rheumatic heart disease
are of sufficient importance to

warrant the urgent attention of
the international public health
and research communities.
Dr. Carapetis is the director of the Menzies
School of Health Research, Charles Darwin
University, Casuarina, Northern Territory,
Australia.
Carapetis JR, Steer AC, Mulholland EK,
Weber M. The global burden of group A
streptococcal diseases. Lancet Infect Dis
2005;5:685-94.
Stollerman GH, Rusoff JH, Hirschfeld I.
Prophylaxis against group A streptococci in
rheumatic fever: the use of single monthly
injections of benzathine penicillin G. N Engl
J Med 1955;252:787-92.
Denny F, Wannamaker LW, Brink WR,
Rammelkamp CH Jr, Custer EA. Prevention
of rheumatic fever: treatment of preceding
streptococcic infection. JAMA 1950;143:
151-3.
Rheumatic fever and rheumatic heart dis-
ease: report of a WHO expert consultation.
World Health Organ Tech Rep Ser 2004;923:
1-122.
McDonald M, Currie BJ, Carapetis JR.
Acute rheumatic fever: a chink in the chain
that links the heart to the throat? Lancet In-
fect Dis 2004;4:240-5.
Copyright © 2007 Massachusetts Medical Society.

1.
2.
3.
4.
5.
Rheumatic Heart Disease in Developing Countries
286pts
AUTHOR
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CASE
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AUTHOR, PLEASE NOTE:
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Please check carefully.
REG F
FILL
TITLE
3rd
Enon

ARTIST:
Carapetis
2 of 2
8-2-07
mst
35705
Still Image from a Two-Dimensional Echocardiogram in a Patient with Moderate
Mitral Regurgitation Due to Rheumatic Heart Disease.
An apical four-chamber view is shown, with color Doppler imaging illustrating a
regurgitant-flow signal that extends along the lateral wall of the left atrium. The blue-
and-yellow mosaic pattern indicates the regurgitant jet (arrow). (Courtesy of Dr.
Andrew Steer, University of Melbourne.)
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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n engl j med

353;7

www.nejm.org august

18, 2005

The

new england journal

of

medicine

671

special article

Sex and Racial Differences in the Management of
Acute Myocardial Infarction, 1994 through 2002

Viola Vaccarino, M.D., Ph.D., Saif S. Rathore, M.P.H., Nanette K. Wenger, M.D.,
Paul D. Frederick, M.P.H., M.B.A., Jerome L. Abramson, Ph.D.,
Hal V. Barron, M.D., Ajay Manhapra, M.D., Susmita Mallik, M.D.,
and Harlan M. Krumholz, M.D., for the National Registry
of Myocardial Infarction Investigators

From the Department of Medicine, Divi-
sion of Cardiology (V.V., N.K.W., J.L.A.) and
Division of General Medicine (S.M.), Em-
ory University School of Medicine; and
the Department of Epidemiology, Rollins
School of Public Health, Emory University
(V.V.), Atlanta; the Section of Cardiovascu-
lar Medicine, Department of Medicine
(S.S.R., H.M.K.), the Division of Health
Policy and Administration, Department of
Epidemiology and Public Health (H.M.K.),
and the Robert Wood Johnson Clinical
Scholars Program (H.M.K.) at Yale Uni-
versity School of Medicine and Yale–New
Haven Hospital Center for Outcomes Re-
search and Evaluation — both in New Ha-

ven, Conn.; the Ovation Research Group,
Seattle (P.D.F.); Genentech, South San
Francisco, Calif. (H.V.B.); and Hackley Hos-
pital, Spring Lake, Mich. (A.M.). Address
reprint requests to Dr. Vaccarino at the De-
partment of Medicine, Division of Cardiol-
ogy, Emory University School of Medicine,
1256 Briarcliff Rd., Suite 1N, Atlanta, GA
30306, or at
N Engl J Med 2005;353:671-82.

Copyright © 2005 Massachusetts Medical Society.

background

Although increased attention has been paid to sex and racial differences in the manage-
ment of myocardial infarction, it is unknown whether these differences have narrowed
over time.

methods

With the use of data from the National Registry of Myocardial Infarction, we examined
sex and racial differences in the treatment of patients who were deemed to be “ideal can-
didates” for particular treatments and in deaths among 598,911 patients hospitalized
with myocardial infarction between 1994 and 2002.

results

In the unadjusted analysis, sex and racial differences were observed for rates of reper-
fusion therapy (for white men, white women, black men, and black women: 86.5, 83.3,

80.4, and 77.8 percent, respectively; P<0.001), use of aspirin (84.4, 78.7, 83.7, and
78.4 percent, respectively; P<0.001), use of beta-blockers (66.6, 62.9, 67.8, and 64.5
percent; P<0.001), and coronary angiography (69.1, 55.9, 64.0, and 55.0 percent;
P<0.001). After multivariable adjustment, racial and sex differences persisted for rates
of reperfusion therapy (risk ratio for white women, black men, and black women: 0.97,
0.91, and 0.89, respectively, as compared with white men) and coronary angiography
(relative risk, 0.91, 0.82, and 0.76) but were attenuated for the use of aspirin (risk ratio,
0.97, 0.98, and 0.94) and beta-blockers (risk ratio, 0.98, 1.00, and 0.96); all risks were
unchanged over time. Adjusted in-hospital mortality was similar among white women
(risk ratio, 1.05; 95 percent confidence interval, 1.03 to 1.07) and black men (risk ratio,
0.95; 95 percent confidence interval, 0.89 to 1.00), as compared with white men, but
was higher among black women (risk ratio, 1.11; 95 percent confidence interval, 1.06
to 1.16) and was unchanged over time.

conclusions

Rates of reperfusion therapy, coronary angiography, and in-hospital death after myo-
cardial infarction, but not the use of aspirin and beta-blockers, vary according to race
and sex, with no evidence that the differences have narrowed in recent years.
abstract
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
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n engl j med

353;7

www.nejm.org august

18

,

2005

The

new england journal

of

medicine

672
n recent years, attention has been

focused on variations in the treatment of coro-
nary heart disease that are related to the sex and
race of the patient. Landmark studies in the late
1980s and early 1990s reported differences in treat-
ment according to sex and race.

1-4

In the past de-
cade, other investigations have described a generally
consistent pattern of less intensive treatment of
acute myocardial infarction in women, as compared
with men,

5-11

and in blacks, as compared with
whites,

8,9,12-17

across a variety of settings. Efforts
to remedy racial and sex differences in health care
use have received prominent attention, including a
recent Institute of Medicine report

18

and the Public
Health Service’s Healthy People 2010 initiative.

19

Although sex and racial differences in the treat-
ment of coronary heart disease have been docu-
mented for more than a decade, little is known
about whether these differences have persisted in
more recent years. We assessed temporal trends in
sex and racial differences in the use of guideline-
based management for patients hospitalized with
acute myocardial infarction.

patients

Since July 1, 1990, hospitals participating in the
National Registry of Myocardial Infarction (NRMI)
have enrolled consecutive patients with myocar-
dial infarction, as previously described.

20

Because
NRMI-1 (July 1990 through May 1994) collected
little information on patients’ characteristics, we
restricted our analysis to the 1,724,984 patients
from 1917 hospitals who were enrolled in NRMI-2
(June 1994 through March 1998), NRMI-3 (April
1998 through June 2000), and NRMI-4 (July 2000
through May 2002). We excluded 12,132 patients
with erroneous discharge dates and 381,018 pa-
tients who were transferred from another acute care
hospital because their early treatments were not
documented. We also excluded 131,474 patients
who survived less than 24 hours because of insuffi-
cient time to begin treatments; 40,881 patients of
unknown age, sex, race, or survival status; 60,689
patients whose race was not recorded as white or
black; and 55,316 patients with missing data for
model covariables. We restricted our analysis to 658
hospitals (out of 1917 hospitals) participating in
NRMI for the full study period, resulting in a final
sample of 598,911 patients. NRMI data collection
has previously been validated by comparison with
the Cooperative Cardiovascular Project.

21

This pro-
tocol was deemed exempt from review by the insti-
tutional review board at Emory University.

treatment of myocardial infarction

Patients were evaluated for the use of treatments
recommended by the American College of Cardi-
ology–American Heart Association (ACC–AHA)
guidelines for the treatment of myocardial infarc-
tion since 1990.

22-24

These included acute reperfu-
sion therapy for patients with ST-segment elevation
within 24 hours of admission, the administration
of aspirin and beta-blockers within 24 hours of ad-
mission, and coronary angiography during hospi-
talization. As secondary treatment end points, we
examined the frequency of coronary-artery bypass
graft (CABG) surgery and percutaneous translumi-
nal coronary angioplasty (PTCA) (except for primary
PTCA, which was included in our definition of re-
perfusion therapy) during hospitalization.
To exclude racial or sex variations in treatment
that may reflect differences in the proportion of pa-

tients for whom treatment is considered appropri-
ate, we identified subgroups of patients who were
ideally suited for each management strategy — in
other words, patients with the strongest indica-
tions for treatment (ACC–AHA class I) and without
major contraindications, according to guidelines
published in 1990,

22

1996,

23

and 1999.

24

When
variations were present in the three sets of guide-
lines, the 1996 guidelines were followed, since they
are similar to the 1999 guidelines and were pub-
lished closest to the beginning of our observation
period.
To avoid bias in regard to the availability of ser-
vices, rates of coronary angiography were calculated
among patients admitted to facilities with full ca-
pability of performing invasive cardiovascular pro-
cedures. Rates of use of CABG and PTCA were cal-
culated among patients admitted to these facilities

who were “ideal candidates” for coronary angiog-
raphy and who underwent angiography. Because
information was lacking on angiographic findings,
we were not able to define further patient eligibility
for revascularization. The only contraindication to
the use of aspirin in the initial management of
myocardial infarction is true allergy to salicylates,
which is uncommon and was not recorded in NRMI.
Therefore, no ideal-candidate subgroup was creat-
ed for aspirin.
i
methods
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sex and racial differences in treatment of myocardial infarction

673

in-hospital mortality

We examined trends in hospital mortality accord-

ing to sex and race. This analysis was restricted to
patients who were not transferred to another acute
care hospital, since the survival status of transferred
patients in the second hospital was unknown.

statistical analysis

We categorized patients into four groups according
to race and sex: white men, white women, black
men, and black women. Sex and racial differences
in demographic and clinical factors and in the char-
acteristics of hospitals were assessed over the full
study period and stratified according to year of treat-
ment (with a year defined as the period from June
through May). We calculated crude rates of treat-
ment and in-hospital mortality for the selected sub-
groups of ideal-candidate patients in the four
groups.
We used logistic-regression models to derive
the likelihood of treatment and death for the four
groups.

25

We tested whether differences in the use
of treatments according to sex and race changed
over time by including a three-way interaction term
reflecting the sex and race of patients and the year.
Three consecutive models were constructed for
each end point. Model 1 included sex, race, year,

and all two-way and three-way interaction terms
among sex, race, and year; model 2 expanded the
data in model 1 to include other demographic and
clinical factors; and model 3 expanded the data in
model 2 to include characteristics of the hospitals.
To assess whether the clustering of patients within
hospitals affected our results, analyses were repeat-
ed with the use of generalized-estimating-equation
models. The results were similar and are not report-
ed. All analyses were performed using SAS software
(version 8.2).

characteristics of patients and hospitals

The mean age of patients did not change substan-
tially over time, but the prevalence of most coro-
nary risk factors increased in all subgroups (Table
1), whereas there was a decline in the proportion of
patients with ST-segment elevation or Q waves on
initial electrocardiography. The four subgroups
showed similar time trends in most factors, as
shown by the nonsignificant interaction among sex,
race, and year. In all years combined, there were
substantial differences in many factors according
to sex and race. For example, women in both racial
groups were older than men, whereas blacks in both
sex groups were younger than whites. As compared
with white men, fewer female and black patients
had ST-segment elevation or Q waves on initial elec-
trocardiography, but women and blacks had more

risk factors, a higher Killip class, and a longer delay
to reach the hospital. As compared with whites,
black patients tended to be hospitalized more often
in facilities that were used for teaching, were affili-
ated with medical schools, were located in urban
areas, and had equipment for performing cardio-
vascular procedures.

ideal candidates for treatments
and procedures

The proportion of patients qualifying as ideal can-
didates for reperfusion and the administration of
beta-blockers was 50 percent or less and declined
over time in all groups. At each time point, women
and blacks were less likely than white men to be ide-
al candidates (Fig. 1). Approximately 10 percent
of patients were classified as ideal candidates for
coronary angiography. This percentage was simi-
lar in all sex and racial groups and fairly constant
over time.

treatments and procedures
among ideal candidates

In the unadjusted analysis, treatment rates differed
according to sex and race, with rates highest in
white men and lowest in black women (Table 2).
Differences were larger for rates of reperfusion ther-
apy and coronary angiography, particularly for black

women, but smaller for the use of aspirin and beta-
blockers. The use of aspirin and beta-blockers in-
creased over time, whereas rates of reperfusion
therapy remained stable and those of coronary an-
giography decreased slightly, with similar time
trends in the four demographic groups. As a result,
there was no significant variation over time in treat-
ment differences according to sex or race.
Results that were adjusted for the characteris-
tics of patients and hospitals were similar (Table 3).
Because models 2 and 3 provided almost identical
results, only the results of model 3 (adjusted for
both patient and hospital characteristics) are pre-
sented. The interaction among the factors of sex,
race, and year, as well as all other pairwise interac-
tions, were not significant, indicating that racial and
results
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The

new england journal

of

medicine

674

Table 1. Demographic and Clinical Characteristics of Hospitalized Patients According to Sex, Race, and Study Year.*
Characteristic White Men White Women Black Men Black Women
P
Value‡

1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years†
1994–
1996
1996–

1998
1998–
2000
2000–
2002
All
Years†
1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years†
1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years†

Patients

Mean age (yr) 65.1 65.9 66.9 67.4 66.4 72.9 73.4 74.4 75.0 74.0 60.5 60.8 61.4 62.0 61.3 66.6 66.8 67.6 67.9 67.3 0.96
Primary medical insurance (%) 0.46
Age <65 yr and commer-
cial insurer or PPO
24.2 21.7 21.8 21.0 22.1 10.9 9.8 9.7 9.5 9.9 21.0 18.1 19.2 18.2 19.0 13.1 10.6 10.5 11.0 11.2
Age <65 and HMO 6.8 8.7 9.6 8.9 8.6 3.2 4.1 4.5 4.2 4.0 8.6 10.9 12.4 11.6 11.0 6.6 6.8 8.2 7.9 7.5
Age <65 yr and Medicaid 1.5 1.4 1.3 1.4 1.4 2.0 1.8 1.7 1.7 1.8 4.7 4.3 4.3 5.0 4.6 7.1 6.9 6.4 5.9 6.5
Age <65 yr and other type
of insurance
10.8 9.5 7.0 6.7 8.4 5.5 4.8 3.4 3.1 4.1 17.7 17.8 14.1 13.1 15.5 10.1 10.7 8.3 7.0 8.8
Medicare, age ≥65 yr 56.7 58.7 60.3 62.0 59.6 78.5 79.4 80.6 81.5 80.1 48.1 48.9 50.1 52.1 49.9 63.0 65.0 66.5 68.2 66.0
Medical history (%)
Myocardial infarction 27.5 27.9 27.5 27.6 27.6 23.6 23.9 23.7 24.0 23.8 24.9 26.5 24.9 26.1 25.6 25.2 25.6 23.0 24.1 24.3 0.04
Angina 18.5 17.7 14.0 12.5 15.5 19.9 18.8 14.1 12.4 15.9 14.2 13.9 11.5 9.2 12.0 16.8 16.6 12.0 9.5 13.2 0.25
Heart failure 10.9 12.1 14.2 15.8 13.4 19.2 20.2 23.3 24.7 22.1 12.5 15.1 18.1 18.7 16.4 21.4 23.0 24.8 27.4 24.5 0.64
PTCA 8.9 10.3 12.3 14.5 11.6 5.6 6.9 8.3 9.6 7.8 6.6 8.0 10.1 11.9 9.5 6.0 6.6 7.7 10.1 7.8 0.54
CABG 14.6 15.8 17.5 18.8 16.8 8.2 9.5 10.2 10.9 9.8 6.6 7.7 9.1 10.2 8.5 5.8 6.4 7.3 8.4 7.2 0.63
Stroke 7.1 8.0 9.3 9.2 8.5 9.8 10.6 12.6 12.4 11.5 9.5 10.2 12.5 12.3 11.3 12.2 14.1 15.4 14.8 14.3 0.17
Diabetes 22.3 23.8 26.4 28.0 25.3 29.8 30.2 32.0 32.2 31.2 31.2 31.0 34.6 34.4 33.0 45.8 47.1 45.4 47.5 46.5 0.36
Hypertension 44.6 47.6 51.3 55.3 49.9 56.5 59.8 63.5 66.8 62.1 62.9 65.9 68.1 70.8 67.3 74.3 77.0 78.5 81.5 78.3 0.61
Current smoking 30.4 29.3 27.3 27.1 28.4 20.1 19.5 18.0 17.6 18.7 39.5 38.6 36.2 36.2 37.5 22.5 22.9 21.9 22.0 22.3 0.04
Hypercholesterolemia 25.8 29.3 32.6 36.4 31.3 24.1 27.0 28.1 30.7 27.7 18.7 22.7 23.4 27.4 23.3 20.4 22.7 23.7 27.2 23.9 0.32
Time from onset of symptoms to arrival at hospital
Mean (hr) 5.3 5.2 5.2 5.1 5.2 6.3 5.9 5.9 5.6 5.9 6.2 5.7 5.9 5.2 5.8 6.5 6.6 6.6 5.9 6.4 0.03
Not available (%) 21.8 25.0 32.1 38.1 29.6 28.7 32.6 40.7 47.4 38.2 26.9 31.9 39.3 46.0 36.8 33.7 39.3 46.4 52.7 44.3 0.26
Chest pain on presentation (%) 76.5 73.7 68.3 66.2 70.9 67.0 64.0 56.5 53.8 59.7 71.8 69.7 65.0 62.8 66.9 64.4 61.6 55.2 54.5 58.2 0.30
Changes in first electrocardiogram (%)
ST-segment elevation 44.8 40.7 33.6 28.3 36.4 40.2 35.6 27.6 22.5 30.7 41.0 38.4 30.5 25.1 33.1 33.6 31.1 23.7 19.2 25.9 0.17
ST-segment depression 28.3 29.4 28.4 27.3 28.3 28.3 29.1 27.6 25.8 27.6 24.6 25.5 23.3 21.8 23.7 23.6 24.7 23.1 20.8 22.9 0.34
Q wave 12.0 10.2 8.7 7.8 9.6 10.8 9.0 7.0 6.5 8.1 9.7 9.1 7.3 6.4 8.0 7.9 7.9 5.4 5.6 6.5 0.32

Left bundle-branch block 5.3 5.6 5.4 3.6 5.0 7.5 7.9 7.6 4.8 6.9 3.5 4.4 3.9 3.0 3.7 6.2 6.0 5.6 3.4 5.1 0.03
Killip class (%) 0.72
1 (No heart failure) 78.9 78.6 78.1 78.1 78.4 67.9 68.3 68.0 68.6 68.2 75.9 76.2 74.2 75.2 75.3 67.1 66.5 68.1 67.6 67.4
2 (Heart failure) 14.2 14.4 14.7 15.0 14.6 20.9 20.8 21.0 21.3 21.0 16.0 15.7 17.3 17.1 16.6 20.2 20.8 19.4 20.8 20.3
3 (Pulmonary edema) 6.1 6.3 6.4 6.1 6.2 10.2 10.0 10.2 9.3 9.9 7.7 7.3 7.8 7.2 7.5 12.0 11.9 11.8 10.9 11.6
4 (Cardiogenic shock) 0.8 0.7 0.8 0.8 0.8 1.0 0.9 0.7 0.8 0.8 0.5 0.7 0.7 0.6 0.6 0.7 0.9 0.7 0.7 0.8
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sex and racial differences in treatment of myocardial infarction

675

* The study period was June to May, so there is overlap in years. HMO denotes health maintenance organization, PPO preferred provider organization, PTCA percutaneous transluminal
coronary angioplasty, and CABG coronary-artery bypass grafting. Because of rounding, not all percentages total 100.
† P<0.01 for the comparison of white men with white women, black men, and black women for all years combined, except for P values for creatinine kinase levels, which were two or more
times the normal level among black men (P=0.33).
‡ P values indicate whether there is a significant difference in the trend over time for factors among the four subgroups defined by sex and race.

§ Volume denotes the number of patients admitted with myocardial infarction per year.
Mean systolic blood pressure
(mm Hg)

144.9 145.1 144.3 143.7 144.5 145.5 146.3 145.6 145.1 145.6 149.9 148.4 147.7 147.6 148.3 150.5 150.9 151.1 151.2 151.0 0.008
Mean pulse (beats/min) 84.2 84.9 86.1 86.4 85.5 89.0 89.8 91.0 91.4 90.4 86.4 87.0 88.9 88.8 87.9 90.0 91.5 92.1 92.2 91.6 0.16
Creatine kinase or creatine
kinase MB ≥2 times
normal (%)
85.6 86.0 80.3 76.2 81.9 82.1 82.3 74.3 69.2 76.5 85.6 85.4 79.5 76.5 81.4 82.7 82.7 75.0 70.4 76.9 0.96
Ejection fraction (%) 0.32
≥0.40 42.1 45.4 47.3 52.2 46.9 38.5 42.9 45.6 50.4 44.8 42.0 43.6 46.4 49.7 45.8 41.7 42.5 46.9 50.3 46.0
<0.40 15.3 17.5 19.4 22.4 18.8 14.7 16.8 18.4 21.6 18.2 17.4 19.9 23.9 26.4 22.3 16.1 19.0 20.0 23.9 20.2
Not assessed 42.6 37.2 33.3 25.4 34.3 46.8 40.3 36.0 28.0 37.0 40.6 36.5 29.8 23.8 31.9 42.2 38.5 33.0 25.8 33.8

Hospitals

Staffed beds >200 (%) 72.9 72.7 73.1 73.7 73.1 71.7 72.4 71.8 72.3 72.1 84.4 85.2 86.5 86.6 85.8 85.6 85.4 86.9 86.8 86.3 0.47
Medical-school affiliation (%) 42.5 43.3 45.3 44.6 44.0 42.4 43.6 44.7 43.6 43.7 55.8 56.6 58.2 58.6 57.4 58.2 59.3 59.9 60.4 59.6 0.95
Teaching facility (%) 8.5 9.7 8.4 8.7 8.8 7.7 9.2 8.1 8.6 8.4 18.0 20.5 17.5 18.7 18.6 19.1 22.6 18.8 18.6 19.7 0.01
Urban location (%) 83.0 82.6 83.7 84.4 83.5 81.9 81.8 82.5 83.3 82.4 88.5 88.4 89.8 91.1 89.6 90.2 88.5 89.8 91.0 89.9 0.08
Facilities for cardiovascular procedures (%) 0.31
None 17.1 15.7 13.8 11.7 14.5 19.0 17.1 15.5 13.8 16.1 9.8 7.9 8.7 7.9 8.5 8.8 7.1 7.9 7.4 7.7
Coronary catheterization
only
27.3 27.3 24.2 20.1 24.6 29.0 28.8 26.4 23.0 26.5 25.9 25.8 23.7 19.4 23.4 25.9 25.9 24.7 20.6 24.0
PTCA, no open heart
surgery
7.1 6.3 5.9 7.3 6.6 7.3 6.4 6.1 7.5 6.8 8.7 6.9 6.2 9.7 7.9 8.4 6.9 7.3 10.5 8.4
PTCA and open heart
surgery
48.5 50.7 56.1 60.8 54.3 44.7 47.7 52.0 55.6 50.5 55.5 59.4 61.4 63.0 60.2 57.0 60.0 60.1 61.4 59.9
Quartile of myocardial-infarction volume (%)§ 0.15
≤79 5.5 4.8 4.0 3.4 4.4 6.0 4.9 4.5 3.9 4.7 3.0 3.0 2.8 2.4 2.8 3.5 2.8 3.6 2.5 3.1

80–135 14.3 13.5 12.2 11.9 12.9 14.7 14.1 13.3 13.4 13.8 14.8 13.9 13.3 11.5 13.2 14.8 12.7 13.4 12.1 13.1
136–228 26.6 25.1 24.8 24.4 25.2 28.1 26.3 25.6 26.0 26.4 32.1 29.4 29.6 28.9 29.9 30.3 31.4 31.7 30.8 31.1
≥229 53.6 56.6 58.9 60.2 57.5 51.2 54.7 56.5 56.8 55.1 50.1 53.7 54.2 57.2 54.1 51.5 53.1 51.3 54.6 52.7
Hospital ownership (%) 0.77
Public 12.6 12.9 11.6 11.0 12.0 12.3 12.4 11.3 10.6 11.6 16.4 19.1 18.6 15.9 17.5 16.6 20.3 17.2 16.8 17.7
Private, not-for-profit 82.5 81.9 82.7 83.5 82.7 83.3 83.0 83.6 84.5 83.6 79.7 75.2 76.7 79.8 77.9 79.3 75.3 78.3 79.6 78.2
Private, for-profit 4.8 5.2 5.7 5.5 5.3 4.4 4.6 5.1 4.9 4.8 3.9 5.7 4.6 4.3 4.6 4.1 4.4 4.6 3.6 4.2
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Figure 1. Proportions of Patients Considered Ideally Suited for Treatments
and Procedures after Acute Myocardial Infarction, According to Sex and Race
by Study Year.

A year was defined in this study as the period from June through May.
White men
White women
Black men
Black women
Percentage of Patients
40
30
10
20
0
1994–1996 1996–1998 1998–2000 2000–2002
50
Percentage of Patients
40
30
10
20
0
1994–1996 1996–1998 1998–2000 2000–2002
50
Percentage of Patients
40
30

10
20
0
1994–1996 1996–1998 1998–2000 2000–2002
Study Year
50
White men
White women
Black men
Black women
White men
White women
Black men
Black women
Reperfusion Therapy
Beta-Blockers
Coronary Angiography

sex differences in treatment did not change over
time. In absolute terms, black women remained the
group with the lowest rate of use of interventions.
As compared with white men, the adjusted risk ra-
tio for the use of reperfusion therapy in all years
combined was 0.97 for white women, 0.91 for black
men, and 0.89 for black women (P<0.001 for all
comparisons). For coronary angiography, corre-
sponding estimates were 0.91, 0.82, and 0.76
(P<0.001 for all comparisons). Adjusted differenc-
es for the use of aspirin and beta-blockers were
small. For the use of aspirin, the risk ratio during

the entire period was 0.97 for white women, 0.98
for black men, and 0.94 for black women, as com-
pared with white men (P<0.001 for all compari-
sons). For the use of beta-blockers, corresponding
figures were 0.98 (P<0.001), 1.00 (P=0.55), and
0.96 (P<0.001). Preferences of patients with respect
to reperfusion therapy were recorded starting in
1998. These data show few refusals for reperfusion
therapy (less than 0.5 percent) in each sex-and-race
subgroup.
Analysis of secondary treatment end points in-
dicated lower rates of use of CABG as compared
with white men, with an adjusted risk ratio of treat-
ment for white women, black men, and black wom-
en of 0.73, 0.74, and 0.63, respectively (P<0.001
for all comparisons). Adjusted differences in rates
of PTCA according to sex and race were small, ex-
cept for black women (risk ratio, 0.89; 95 percent
confidence interval, 0.83 to 0.95); white women had
slightly higher rates of PTCA than did white men
(risk ratio, 1.06; 95 percent confidence interval,
1.04 to 1.08). Data on the use of stents were avail-
able starting in 1998. There was a steady increase
in stent use over time, from 73.1 percent in 1998 to
87.3 percent in 2000 through 2002. Similar propor-
tions of patients undergoing PTCA received stents
regardless of sex or race, with similar time trends.
Racial and sex differences in the use of CABG and
PTCA did not change over the study period.

mortality

Overall, 21.7 percent of patients were transferred
to other hospitals and excluded from assessment
of in-hospital mortality. The proportion of patients
who were transferred varied among groups accord-
ing to race and sex: 23.2 percent for white men,
18.0 percent for white women, 18.3 percent for
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sex and racial differences in treatment of myocardial infarction

677


* The study period was June to May, so there is overlap in years. CABG denotes coronary-artery bypass grafting and PTCA percutaneous transluminal coronary angioplasty.
† Patients were considered ideal candidates for reperfusion therapy if they were less than 75 years of age, had ST-segment elevation on the first echocardiogram, presented within 12 hours
after the onset of symptoms, did not have documented contraindications to fibrinolytic therapy (i.e., active internal bleeding or known bleeding diathesis; a history of stroke, recent sur-
gery, or trauma; intracranial neoplasm; severe uncontrolled hypertension; or other documented contraindication), and did not decline to receive treatment.
‡ Patients were considered ideal candidates for beta-blocker therapy if they had a pulse of at least 60 beats per minute; did not have evidence of heart failure, shock, or hypotension (i.e., sys-
tolic blood pressure <100 mm Hg); and presented within 12 hours after the onset of symptoms.

§ Patients were considered ideal candidates for coronary angiography if they were admitted to hospitals fully able to perform invasive procedures and if they had had any of the following
conditions: hypotension requiring intervention, recurrent angina, ischemia or infarction, cardiogenic shock, and hemodynamic instability.

¶Patients were considered ideal candidates for coronary angiography and had undergone the procedure.

Table 2. Unadjusted Rates of Treatments, Procedures, and Outcomes among Hospitalized Patients, According to Sex, Race, and Study Year.*
Characteristic White Men White Women Black Men Black Women

1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years
1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years
1994–
1996

1996–
1998
1998–
2000
2000–
2002
All
Years
1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years

percent

Primary treatment end points
Reperfusion therapy in first 24 hr
for ideal candidates†
87.4 87.4 84.1 86.8 86.5 84.9 83.8 81.6 82.6 83.3 80.4 80.8 79.8 80.7 80.4 79.6 78.4 74.5 78.8 77.8
Aspirin in first 24 hr, all patients 80.7 85.4 86.8 84.2 84.4 73.5 80.1 81.3 78.8 78.7 79.5 84.1 85.1 84.5 83.7 72.2 79.8 80.4 79.3 78.4
Beta-blockers in first 24 hr for ideal
candidates

‡

54.7 63.2 69.3 79.7 66.6 49.7 59.7 65.6 76.0 62.9 57.1 62.9 71.2 80.0 67.8 49.8 60.7 69.1 75.6 64.5
Coronary angiography for ideal can-
didates§
72.3 72.3 67.0 65.4 69.1 58.0 59.7 54.5 52.7 55.9 68.5 65.6 62.0 61.1 64.0 59.5 56.4 54.8 51.1 55.0
Secondary treatment end points
CABG (excluding immediate CABG)
for catheterized patients¶
25.5 26.6 26.4 28.1 26.7 22.4 22.3 23.1 23.3 22.8 19.5 21.6 20.5 22.7 21.1 15.9 18.2 23.7 20.4 19.8
PTCA (excluding primary procedure)
for catheterized patients¶
44.5 45.0 48.2 46.7 46.1 43.6 45.1 46.6 44.5 45.0 39.6 44.7 48.5 43.0 44.0 39.8 33.4 37.8 41.5 38.1
In-hospital mortality for all patients 8.8 8.5 9.1 8.8 8.8 13.7 12.3 12.2 11.4 12.3 6.8 6.8 7.5 7.8 7.3 10.5 10.5 11.3 10.5 10.7
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18

,

2005

The

new england journal

of

medicine

678

black men, and 14.4 percent for black women
(P<0.001). Among patients who remained in the
same hospital, overall unadjusted mortality was
10.2 percent, ranging from 7.3 percent among black
men to 12.3 percent among white women (Table 2).
After adjustment for differences in age and other
characteristics of patients and hospitals, the death
rate in hospitals was similar among black men (risk
ratio as compared with white men, 0.95; 95 percent
confidence interval, 0.89 to 1.00) and white wom-
en (risk ratio, 1.05; 95 percent confidence interval,
1.03 to 1.07), but higher among black women (risk
ratio, 1.11; 95 percent confidence interval, 1.06 to
1.16). Racial and sex differences did not change
over time.
There were notable differences and similarities in
the treatment and outcome of myocardial infarc-
tion according to race and sex from 1994 through
2002. As compared with white men, fewer black
men and black women received reperfusion thera-
py and coronary angiography, whereas black wom-
en had the highest adjusted mortality rate among

all sex and racial groups. In contrast, differences in
treatment and mortality between white women and
white men were generally small, as were differenc-
es between any of the four racial and sex groups in
the use of aspirin and beta-blockers. Racial and sex
differences were essentially unchanged between
1994 and 2002.
Management differences were greater when pa-
tients were compared according to race within each
sex (black men vs. white men and black women vs.
white women) than when they were compared ac-
cording to sex within each race (black men vs. black
women or white men vs. white women), suggest-
ing that disparities according to race may be more
important than disparities according to sex. Black
women had the highest risk of not receiving reper-
fusion therapy and coronary angiography. Several
previous studies also documented less aggressive
management of coronary disease in both wom-
en

5-11

and blacks.

8,9,12,14,15

The few studies that
examined subgroups classified according to both
sex and race also found the lowest rates among

black women.

13,26,27

Treatment differences according to sex and race
persisted without much variation between 1994 and
2002. Although several studies investigated time
trends in management of acute myocardial infarc-
discussion

Table 3. Unadjusted and Adjusted Risk Ratios for Treatments, Procedures, and Outcomes among Hospitalized Patients Classified According to Sex, Race, and Study Year. *
Characteristic White Women Black Men Black Women P Value† P Value‡

1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years§
1994–
1996
1996–
1998
1998–
2000
2000–

2002
All
Years§
1994–
1996
1996–
1998
1998–
2000
2000–
2002
All
Years§

risk ratio

Primary treatment end points

Reperfusion therapy in first 24 hr for ideal candidates
Unadjusted 0.97 0.96 0.97 0.95 0.96 0.92 0.92 0.95 0.93 0.93 0.91 0.90 0.89 0.91 0.90 0.34 0.68
Adjusted

¶

0.98 0.97 0.98 0.95 0.97 0.90 0.91 0.94 0.90 0.91 0.91 0.90 0.87 0.89 0.89 0.26 0.67
Aspirin in first 24 hr for all patients
Unadjusted 0.91 0.94 0.94 0.94 0.93 0.98 0.98 0.99 1.00 0.99 0.90 0.93 0.93 0.94 0.93 0.30 0.56
Adjusted

¶

0.96 0.97 0.97 0.97 0.97 0.97 0.97 0.98 1.00 0.98 0.90 0.94 0.93 0.96 0.94 0.55 0.38
Beta-blockers in first 24 hr for ideal candidates
Unadjusted 0.91 0.94 0.95 0.95 0.94 1.04 0.99 1.03 1.00 1.02 0.91 0.96 1.00 0.95 0.97 0.80 0.78
Adjusted

¶

0.96 0.98 0.98 0.98 0.98 1.00 0.96 1.00 1.00 1.00 0.88 0.95 0.98 0.96 0.96 0.38 0.75
Coronary angiography for ideal candidates
Unadjusted 0.80 0.83 0.81 0.81 0.81 0.95 0.91 0.92 0.93 0.93 0.82 0.78 0.82 0.78 0.80 0.07 0.62
Adjusted¿ 0.91 0.93 0.93 0.89 0.91 0.82 0.78 0.84 0.86 0.82 0.82 0.73 0.77 0.77 0.76 0.055 0.25
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18, 2005

sex and racial differences in treatment of myocardial infarction

679

* Patients were considered ideal candidates for reperfusion if they were less than 75 years of age, had ST-segment elevation on the first echocardiogram, presented within 12 hours after the
onset of symptoms, did not have documented contraindications to fibrinolytic therapy (i.e., active internal bleeding or known bleeding diathesis; history of stroke, recent surgery, or trau-
ma; intracranial neoplasm; severe uncontrolled hypertension; or other documented contraindication), and did not decline to receive treatment. The study period was June to May, so there

is overlap in years. CABG denotes coronary-artery bypass grafting, and PTCA percutaneous transluminal coronary angioplasty.
† P values are for the interaction between sex and race.
‡This P value indicates whether there is a significant difference in the trend over time for treatments or procedures among the four subgroups defined by race and sex.
§ P<0.01 for the comparison of white men with white women, black men, and black women, for all years combined, except for beta-blockers in black men (unadjusted P =0.05; adjusted
P=0.55), PTCA in black men (unadjusted P=0.09; adjusted P=0.26), PTCA in white women (unadjusted P=0.02), and mortality in black men (adjusted P=0.06).

¶

Risk ratios were adjusted for age, insurance status, medical history (a history of myocardial infarction, angina, heart failure, stroke, diabetes, hypertension, or hypercholesterolemia; cur-
rent smoking status; and previous CABG or PTCA), severity characteristics on admission (Killip class, systolic blood pressure, pulse, chest pain, left bundle-branch block, creatine kinase
levels, location of anterior or septal infarct, and left ventricular ejection fraction [classified as <40 percent, ≥40 percent, or missing]), time from the onset of symptoms to hospital arrival
(<3 hours, 3 to 6 hours, >6 to 12 hours, >12 hours, or not available), and hospital characteristics (number of beds; medical-school affiliation or teaching status; urban location; availability
of invasive procedures, including catheterization, CABG, and PTCA; annual quartiles for the volume of myocardial infarction, and hospital ownership [including public, private not-for-prof-
it, and private for-profit]).
¿ Risk ratios were adjusted for the same factors as those listed above, except that availability of invasive procedures was not included among hospital characteristics, since only patients ad-

mitted to hospitals fully able to perform invasive procedures were examined for the use of cardiovascular procedures.

Secondary management end points

CABG (excluding immediate CABG)
among catheterized patients
Unadjusted 0.88 0.84 0.88 0.83 0.85 0.76 0.81 0.78 0.81 0.79 0.62 0.68 0.90 0.73 0.74 0.89 0.42
Adjusted¿ 0.76 0.71 0.77 0.71 0.73 0.69 0.78 0.73 0.77 0.74 0.50 0.57 0.78 0.63 0.63 0.88 0.41
PTCA (excluding primary procedure)
among catheterized patients
Unadjusted 0.98 1.00 0.97 0.95 0.98 0.89 0.99 1.01 0.92 0.95 0.89 0.74 0.78 0.89 0.83 0.08 0.52
Adjusted¿ 1.06 1.10 1.04 1.04 1.06 0.92 0.99 1.02 0.92 0.97 0.98 0.79 0.81 0.94 0.89 0.049 0.48

In-hospital mortality for all patients

Unadjusted 1.52 1.42 1.33 1.29 1.38 0.77 0.81 0.82 0.88 0.82 1.19 1.23 1.24 1.19 1.21 0.80 0.72
Adjusted

¶

1.10 1.10 1.01 0.99 1.05 0.92 0.94 0.92 0.99 0.95 1.03 1.11 1.14 1.11 1.11 0.73 0.31
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