The impact of gender on the treatment and outcomes of patients with early reinfarction after fibrinolysis: insights from ASSENT-2
Michael C. Tjandrawidjajaa,
Yuling Fua,
Shaun G. Goodmanb,
Frans Van de Werfc,
Christopher B. Grangerd and
Paul W. Armstronga,* for the ASSENT-2 Investigators
a Department of Medicine, Division of Cardiology, 2-51 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada
b Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
c Universitaire Ziekenhuizen Leuven, Leuven, Belgium
d Duke Clinical Research Institute, Durham, NC, USA
* Corresponding author. Tel.: +1-780-492-0591; fax: +1-780-492-9486
E-mail address: paul.armstrong{at}ualberta.ca
Received 27 November 2002;
revised 14 January 2003;
accepted 14 January 2003
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Abstract
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Aims To assess gender differences in patients with early reinfarction after fibrinolysis for acute myocardial infarction (AMI) and the impact of these differences on treatment and outcomes.
Methods and results We studied 3.7% of men
and 4.8% of women
with early reinfarction after fibrinolysis for AMI in the ASSENT-2 trial of 16,949 patients. Women with reinfarction were older and more often had hypertension, diabetes, and major bleeding prior to reinfarction. Despite adjustment for these differences, women with reinfarction were less likely to receive repeat fibrinolytic therapy (OR: 0.55; 95% CI: 0.370.84). Aggressive treatment by either repeat fibrinolysis or urgent revascularization was associated with reduced 1-year mortality irrespective of gender. Death within 24h of reinfarction was more frequent in women and accounted for a greater proportion of their 1-year mortality (56.0 vs 34.8%;
. The excess mortality in women at 1 year (27.3 vs 19.9%;
was eliminated after adjustment for gender differences in baseline risk profile.
Conclusion Women with early reinfarction following fibrinolysis for AMI had more frequent early death and were managed less aggressively. These findings suggest the need for increased awareness and timely intervention in these patients.
Key Words: Gender Myocardial infarction Reinfarction Trials Fibrinolysis Revascularization
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1. Introduction
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Controversy exists as to the existence of a gender bias in the use of fibrinolysis and invasive procedures for acute myocardial infarction (AMI) in eligible women.19 Nevertheless, prior studies have been unanimous in showing increased morbidity and both short and long term mortality rates in women with AMI.2,4,7,8,1015 The majority have indicated that this higher mortality can be attributed to prognostically worse baseline characteristics in women including older age and a greater burden of comorbidities.2,4,7,8,1015
Recent trials of fibrinolytic therapy have aroused increased interest in the issue of early reinfarction i.e. during hospitalization after AMIoccurring in approximately 4% of patientsas it relates to its prevention, treatment, and survival implications.1620 Fibrinolysis given in combination with GP IIb/IIIa blockers (i.e. abciximab) or new-generation anticoagulants (i.e. enoxaparin, bivalirudin) has been shown to lower the incidence of early reinfarction relative to standard fibrinolytic monotherapy.1618 For patients who sustain early reinfarction, it has been shown that aggressive treatment by either repeat fibrinolysis or urgent interventional revascularization may improve prognosis.19 The importance of these promising results relates to the considerably worse outcomes of patients with early reinfarction vs those without, recently confirmed by combined analysis of the GUSTO-I and III trials (30-day mortality: 11.3 vs 3.5%; 30-day to 1-year mortality: 4.7 vs 3.2%)20 and by the more recent GUSTO-V trial (1-year mortality: 22.6 vs 8.0%; Lincoff AM et al., presented at XIVth World Congress of Cardiology, Sydney 2002).
Limited data exists regarding gender differences in patients who sustain early reinfarction. Combined analysis of the GUSTO-I and III trials have shown that women are significantly more likely than men to sustain early reinfarction.20 Accordingly, the large ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic) trial of fibrinolytic therapy in 16,949 AMI patients provided the unique opportunity to systematically evaluate gender differences among patients with early reinfarction relating to: (1) baseline profile and in-hospital course, (2) the treatment of reinfarction with particular reference to repeat fibrinolysis and revascularization, and (3) 30-day and 1-year mortality.21
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2. Methods
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The ASSENT-2 trial has been previously described in detail.21 Briefly, 16,949 patients were randomly assigned to receive either an accelerated infusion of alteplase (t-PA) or single-bolus injection of tenecteplase (TNK-tPA) if they had onset of symptoms of AMI within 6h before randomization and ST-segment elevations
0.1mV in at least two limb leads, or
0.2mV in at least two contiguous precordial leads, or the presence of left bundle branch block. There were no protocol-specified contraindications to enrollment.
2.1. Definitions
This study comprises the 670 patients (4.0%) who sustained early reinfarction i.e. during the index hospitalization following fibrinolysis (Fig. 1). The diagnosis of reinfarction was determined by site investigators based upon conventional protocol-specified criteria:1618,21
-
, reinfarction was defined by recurrent signs and symptoms of ischemia at rest accompanied by new or recurrent ST-segment elevations of 0.1mV in at least two contiguous leads that persisted for at least 30min.
-
, reinfarction was defined by the appearance of new Q waves (by Minnesota Code Criteria) in
2 leads, new left bundle branch block, and/or enzyme evidence of reinfarction, which was defined as re-elevation of creatine kinase-MB (CK-MB) to above the upper limit of normal and increased by
50% over the previous value. If CK-MB was not available, the total CK was evaluated; this measurement had to be either re-elevated to at least 2x the upper limit of normal and increased by at least 25%, or re-elevated to
200U/ml over the previous value; if it was re-elevated to less than 2x the upper limit of normal, the total CK had to exceed the upper limit of normal by at least 50% and exceed the previous value by 2-fold or to be re-elevated to
200U/ml.
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, reinfarction was defined as CK-MB (or CK, if MB was not available) more than 2x the upper limit of normal and at least 50% greater than the previous value and/or new Q waves (Minnesota Code) in
2 contiguous leads.
, reinfarction was defined as a CK-MB (or CK, if MB is not available) >5x the upper limit of normal and at least 50% greater than the previous value and/or new Q waves in
2 contiguous leads.

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Fig. 1 Disposition of ASSENT-2 patients by reinfarction status and gender. Mortality rates at 30 days and 1 year.
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The treatment of reinfarction was at the discretion of the treating physicians. For purposes of this analysis, patients with reinfarction were divided into the following three groups: (1) those whoreceived repeated fibrinolytic therapy (repeat fibrinolysis group,
, (2) those who underwent PTCA or CABG the same or next day after reinfarction and did not receive repeat fibrinolysis (urgent revascularization group,
, and (3) those who received neither repeat fibrinolysis nor urgent revascularization (conservative group,
.19
Major bleeding in ASSENT-2 included any bleeding requiring transfusion regardless of hemodynamic status, any intracranial bleed, and bleeding with hemodynamic compromise requiringintervention (e.g. transfusion, inotropic support, ventricular assist device, surgery).
2.2. Analysis of baseline and reinfarction ECGs
Baseline and reinfarction ECGs were evaluated at a core laboratory without knowledge of treatment assignment and clinical outcomes. Reinfarction ECG tracings were available for 471 (70.3%) of the 670 patients.
On both baseline and reinfarction ECGs, infarct location was determined according to previouscriteria22,23 by the presence of ST-segment elevations
0.1mV in at least two contiguous leads and was designated anterior for ST-elevation in leads V1V4and inferior for ST-elevation in leads II, III, and aVF. In cases of ST-elevation in leads I, aVL, V5, and V6, the location was designated anterior unless ST-elevation was also present in leads II, III, aVF, in which case the location was designated inferior. Cases with evidence for both anterior and inferior infarction were recorded as such (anterior+inferior).
The amount (
) of ST-elevation and depression was measured manually 20ms after the J point using a hand-held caliper. The
ST-segment elevation was measured from leads I, aVL, and V1V6for anterior and leads II, III, aVF, I, aVL, V5and V6for inferior myocardial infarction according to previous criteria.23 For the
ST-deviation, the
ST-depression in leads II, III, aVF for anterior and that in leads V1V4 for inferior myocardial infarction were added to the
ST-elevation.23 The extent of epicardial injury was also quantified by counting the number of leads with ST-elevation
0.1mV.
2.3. Statistical analysis
Continuous variables were expressed as either median with 25th75th percentiles or mean±SD and compared with either a MannWhitney Utest or ttest. Categorical data were presented as percentages (with absolute numbers whereappropriate) and compared with the chi-square test. KaplanMeier curves were used to compare times to the occurrence of death between men and women. Multivariate logistic regression was used to evaluate gender differences in the use of particular treatment strategies for reinfarction controlling for differences in baseline characteristics, early in-hospital events/complications prior to reinfarction, and reinfarction ECG characteristics. Logistic regression was also used to evaluate the impact of gender on 30-day and 1-year mortality after adjustment for baseline characteristics and reinfarction treatment strategy.
All tests were 2-sided and
was considered statistically significant. All analyses were performed using SPSS 11.0.1. One-year mortality data is 94.2% complete.
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3. Results
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Fig. 1 shows the distribution of patients in ASSENT-2 by reinfarction status and gender. Both men and women with reinfarction had considerably higher 30-day and 1-year mortality rates than their counterparts without reinfarction.
3.1. Classification of reinfarction according to the ASSENT-2 criteria
Tables 1A and 1B show the distribution of patients and mortality rates, respectively, according to the three ASSENT-2 diagnostic criteria for reinfarction. Overall, 25.5% of reinfarction patients had recurrent ST-elevation suggesting reinfarction
18h post-fibrinolysis and 56.7% of patients had enzymatic evidence for reinfarction >18h post-fibrinolysis. The overall rate of peri-procedural reinfarction was low (3.0%). There were no significant gender differences in the distribution of patients across diagnostic criteria. In addition, the 1-year mortality of reinfarction patients with recurrent ST-elevation
18h was less than that of patients with enzymatic evidence of reinfarction >18h (17.9 vs 25.6%;
. The higher mortality in women vs men with reinfarction was consistent across diagnostic criteria except for the 20 patients with peri-procedural reinfarction.
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Table 1 Distribution of patients and mortality rates according to the ASSENT-2 diagnostic criteria for reinfarction
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3.2. Baseline/presenting characteristics and in-hospital events prior to reinfarction
Overall, 670 of the 16,949 patients (4.0%) in ASSENT-2 sustained in-hospital reinfarction following fibrinolytic therapy. A higher incidence of reinfarction was observed in women vs men (4.8% vs. 3.7%;
). Table 2 presents the baseline and presenting characteristics of patients with reinfarction according to gender. Women were on average five years older than men and had a higher incidence of hypertension and diabetes. Men were more likely to be ex-smokers and to have a history of previous MI. There were no significant gender differences in Killip class, MI location, heart rate, and systolic blood pressure on admission. Time from symptom onset to fibrinolytic treatment was on average 24min delayed in women relative to men. After fibrinolysis for the index MI and prior to reinfarction, women more often sustained both major bleeding (10.1 vs 4.4%;
and minor bleeding (19.2 vs 12.7%;
. Within this early in-hospital period prior to reinfarction, there were no gender differences observed in the use of invasive cardiac procedures and the incidence of intracranial hemorrhage, shock, congestive heart failure, stroke, major arrhythmias, recurrent angina and recurrent ischemia.
3.3. Clinical and ECG characteristics of reinfarction
Reinfarction occurred a median (with 25th75th percentiles) of 3 (15) days after fibrinolysis for the index MI in both men and women. Table 3 shows a comparative analysis of infarct location, ECG indices of myocardial territory at risk, and peak CK measurements of both the index MI and reinfarction. Overall, 15.2% of patients had reinfarction in a separate location relative to the index MI. There were no significant gender differences related to infarct location on either baseline or reinfarction ECGs. Reinfarction in a location separate from the index MI occurred with a comparable frequency in men and women. Although identical at entry, women had less severe ECG evidence of ischemia associated with subsequent reinfarction compared to men (
ST-deviation: 11.4±7.2 vs 13.3±9.4;
. Peak CK measurements of either the index MI or reinfarction were identical in men and women.
3.4. Treatment of reinfarction
Of the 670 patients with reinfarction, 37.8% were treated with repeat fibrinolysis, 28.5% with urgent revascularization on the same or next day, and 33.4% with conservative management. Fig. 2presents gender differences in the treatment strategies for reinfarction. Women with reinfarction were managed conservatively more often than men (unadjusted OR: 1.8; 95% CI: 1.32.6) and were less likely to receive repeat fibrinolytic therapy (unadjusted OR: 0.65; 95% CI: 0.460.93). Among patients who received repeat fibrinolysis, there was no significant gender difference in the proportion (14.6% overall) that underwent revascularization on the same or next day. Overall, urgent revascularization was performed with a similar frequency in men and women. Intra-aortic balloon pumping (IABP) was used in 5.2% of patients and tended to be utilized more often in women (7.9 vs 4.2%;
.
Table 4 shows the clinical characteristics of patients receiving a particular treatment strategy for reinfarction after multivariate analysis incorporating both baseline characteristics and early in-hospital events prior to reinfarction. Patients managed conservatively were female (OR: 1.71; 95% CI: 1.142.57), older, in Killip class >I at entry, more likely to have undergone invasive procedures prior to reinfarction, and more likely to have either major or minor bleeding prior to reinfarction. Table 4 also demonstrates that after multivariate adjustment, women remained less likely than men to receive repeat fibrinolysis for reinfarction (OR: 0.55; 95% CI: 0.370.84).
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Table 4 Adjusted odds ratios with 95% confidence intervals for receiving a particular treatment strategy after reinfarction
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Amongst the reinfarction patients with ECG data, the
ST-deviation was lower among patients managed conservatively (10.9±7.2) compared to those treated with either repeat fibrinolysis (13.7±10.0;
or urgent revascularization (13.2±8.2;
. Recurrent ST changes consistent with impending reinfarction in a separate location from the index MI was more frequent among patients managed conservatively (23.5%) compared to those who received either repeat fibrinolysis (10.9%;
or urgent revascularization (13.7%;
.
In a multivariate analysis adjusting for both clinical and ECG variables amongst those patients in whom this information is available
, women with reinfarction remained less likely to receive repeat fibrinolysis (OR: 0.56; 95% CI: 0.340.94) and overall still tended to be managed conservatively (OR: 1.7; 95% CI: 1.03.0). In addition, a conservative management approach was more likely to be utilized in patients with less severe ischemia on the ECG portending reinfarction and in patients with reinfarction at a distance.
3.5. Outcomes of reinfarction
Table 5 compares the clinical outcomes of reinfarction between men and women. Women were significantly more likely to sustain EMD, major bleeding, and bleeding requiring transfusion. Women tended to experience more frequent congestive heart failure, ventricular fibrillation, asystole, and sustained hypotension compared to men. Overall rates of stroke (0.4%) and intracranial hemorrhage (0.6%) after reinfarction were low.
Major/minor bleeding occurred significantly more often in patients who received either repeat fibrinolysis (7.9%/21.3%) or urgent revascularization (12.5%/20.3%) compared to those managed conservatively (4.4%/12.0%;
for reinfarction. Among those treated with repeat fibrinolysis, women tended to experience more frequent major bleeding (13.8 vs 6.2%;
and bleeding requiring transfusion (12.1 vs 3.1%;
than men. Women treated with urgent revascularization also tended to have more frequent bleeding requiring transfusion than their male counterparts (18.4 vs 7.7%;
.
Death within 24h of reinfarction occurred in 8.8% of patients and was more frequent among patients managed conservatively (18.2%) than among those who received either repeat fibrinolysis (4.3%;
or urgent revascularization (3.6%;
. The median (with 25th75th percentiles) time to death after reinfarction was 2 days earlier in women [0 (03) days] than men [2 (019) days;
. Women managed conservatively were more than twice as likely as their male counterparts to die within 24h of reinfarction (28.0 vs 12.0%;
, a finding not apparent in the groups treated aggressively. Mortality within 24h of reinfarction accounted for a significantly greater proportion of the 1-year mortality in women compared to men (56.0 vs 34.8%;
.
The crude 30-day and 1-year mortality rates among all patients with reinfarction were 16.9 and 22.0%, respectively, and were significantly higher in women than men (Table 5). Fig. 3presents the 1-year KaplanMeier survival curves for men and women. The gender difference in mortality was evident early on and remained significant up to 1 year (log rank
.

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Fig. 3 KaplanMeier survival curves for men and women with reinfarction. Log rank test shows for comparison between men and women.
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Fig. 4depicts the crude and adjusted 1-year mortality rates of patients with reinfarction, according to gender and reinfarction treatment strategy. Crude mortality rates were higher than the adjusted rates among patients managed conservatively whereas the opposite was true among patients treated aggressively with either repeat fibrinolysis or urgent revascularization. Both men and women derived comparable benefit from an aggressive vs conservative approach to treatment, expressed as low (i.e. <1) baseline-adjusted odds ratios for 1-year mortality (men, OR: 0.34, 95% CI: 0.200.59; women, OR: 0.36, 95% CI: 0.160.82). Across all treatment categories, there were no significant differences in 1-year adjusted mortality rates between men and women.

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Fig. 4 Crude and adjusted (i.e. for baseline characteristics) 1-year mortality rates according to gender and reinfarction treatment strategy. Among patients managed conservatively, crude mortality rates were higher than the adjusted rates. However, crude mortality rates were lower than the adjusted rates for patients treated with repeat fibrinolysis or urgent revascularization.
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Fig. 5shows the odds ratios for mortality (i.e. women vs men) adjusting for baseline characteristics as well as reinfarction treatment strategy. At both 30 days and 1 year, adjustment for baseline risk profile eliminated the excess mortality in women observed initially. Additional adjustment for reinfarction treatment strategy further diminished the apparent survival disadvantage in women observed at the outset.

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Fig. 5 Unadjusted and adjusted odds ratios for mortality (women vs men) at 30 days and 1 year by logistic regression analysis.
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4. Discussion
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The principal novel finding of this study is that gender differences influenced the treatment and outcomes of patients who sustained early reinfarction after fibrinolysis for AMI. Despite evidence for a survival benefit associated with aggressive treatment for reinfarction, women were treated with repeat fibrinolysis significantly less often than men. The overall tendency toward conservative management of women with reinfarction was related to but not completely explained by the worse baseline profile, higher frequency of prior fibrinolytic-related bleeding, and less severe ischemia on the ECG portending reinfarction in women compared to men. Women with reinfarction had a more adverse in-hospital course and considerably higher early mortality that was maintained up to 1 year. This gender difference in mortality was largely due to the worse baseline risk profile in women.
The diagnosis of early reinfarction may be difficult in the setting of concurrently evolving ECG and cardiac enzyme changes of the index MI. The present study classified reinfarction events according to three conventional protocol-specified diagnostic criteria. This was done to address possible gender differences in the distribution of patients across these criteria that in turn could modulate differences in outcomes. Interestingly, reinfarction with enzymatic evidence of myocardial damage conferred higher mortality at 30 days and 1 year compared to reinfarction diagnosed according to ECG changes alone. These findings provide new insight into the prognostic implications of differing definitions of reinfarction in the fibrinolytic era. In particular, reinfarction patients with enzymatic evidence defined >18h post-fibrinolysis had an excess mortality of approximately 40% relative to those with recurrent ST-elevation
18h post-fibrinolysis. This finding suggests that in some patients, early recurrent ST-elevation may have been associated with etiologies other than reinfarction i.e. coronary vasospasm, pericarditis, and ventricular aneurysm. Notwithstanding these observations, there were no significant gender differences in the distribution of patients across the three diagnostic criteria.
This study is the first to systematically evaluate in a large number of patients the myocardial territory at risk evident on the ECG portending early reinfarction. The majority of patients in this study (85%) had recurrent ECG changes in the same territory as that of the index MI. This stands in contrast to studies from the pre-fibrinolytic era that have suggested recurrent ischemia more commonlyoccurs in a separate territory from that of the index MI i.e. at a distance (6070%).24, 25
The gender discordance in the use of aggressive treatment for reinfarction in the present study was largely due to the less frequent use of repeat fibrinolytic therapy in women. The risk of major bleeding represents the primary concern among physicians who administer fibrinolysis. This is especially the case when considering a repeat administration close in time to fibrinolysis for the index MI. Although the timing of reinfarction from the index MI was similar between genders, women more often had major bleeding in-hospital prior to reinfarction. The objectively less severe ischemia on the ECG portending reinfarction in women could have also played a role in the decision towards a more conservative, watchful waiting approach in certain patients. However, despite adjustment for gender differences in baseline risk profile, prior major bleeding, and ECG presentation of reinfarction, women remained less likely to receive repeat fibrinolysis. Unknown gender differences in other associated clinical findings at the time of reinfarction e.g. level of anticoagulation, systolic blood pressure, might have accounted for this apparent gender bias. Further investigation of these issues is required to ascertain whether or not a true gender bias exists in the treatment of reinfarction.
Patients with early reinfarction in the GUSTO-I and ASSENT-2 trials derived comparable survival benefit at 30 days from receiving either repeat fibrinolysis or urgent revascularization relative to conservative management.19 The present study indicates that the survival benefit associated with aggressive treatment is maintained up to 1 year irrespective of gender. However, bleeding complications were more frequent after either repeat fibrinolysis or urgent revascularization and were comparable between the two aggressive treatment modalities. Women treated aggressively were more than twice as likely as their male counterparts to sustain major bleeding and to require transfusions. The low overall event rates for stroke and intracranial hemorrhage after reinfarction are encouraging, but did not allow robust comparisons to be made between treatment strategies and between genders for these important safety concerns. Apart from confirming the need to carefully consider the risk-to-benefit ratio associated with aggressive treatment for reinfarction, these results underscore the added importance of such consideration in women.
Previous studies have already documented the considerably increased morbidity and mortality associated with reocclusion of a successfully reperfused infarct-related artery, recurrent ischemia, and early reinfarction after AMI.20,26,27 The present study shows that morbidity and mortality associated with reinfarction was more pronounced in women than men. However, as early as 30 days, the excess mortality in women with reinfarction was already largely explained by their worse baseline risk profile. This finding affirms the importance of the baseline profile in further risk-stratifying patients with reinfarction.28 Another key finding in the present study is that early death within 24h of reinfarction was common, accounted for 42.4% of the 1-year mortality, and occurred more frequently in women. Over 50% of the 1-year mortality in women occurred within 24h of reinfarction. These findings emphasize the need to recognize and respond promptly to the symptoms and clinical signs suggestive of early reinfarction with the goal of reducing early morbidity and mortality. Such vigilance is of particular importance in women where the ECG changes may not be as impressive and belie the increased risk of early death.
The present study is subject to the limitations of post hoc subgroup analysis. Although reinfarction was a prespecified endpoint in ASSENT-2, the treatment of reinfarction was at the discretion of site investigators. Nevertheless, it is noteworthy that equal application of inclusion criteria to all patients enrolled in ASSENT-2 provided initial common ground for the assessment of gender differences in the subsequent treatment and outcomes of patients with early reinfarction. Whereas the ECG data in this study was available in the majority of reinfarction patients i.e. 70%, potentially different findings amongst those in whom data was missing cannot be excluded. This, however, seems unlikely given that the relative mortality differences between men and women were preserved in such patients.
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5. Conclusion
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The present study highlights the distinctive characteristics of men and women who sustained early reinfarction after fibrinolysis for AMI in terms of presentation, treatment, clinical course, and 1-year outcomes. The tendency toward lesser use of repeat fibrinolysis in women occurred in the setting of a comparable survival benefit associated with aggressive treatment in both genders. The considerably increased morbidity and mortality that was associated with reinfarction was more prominent in women but largely related to their worse baseline risk profile. Further studies should address the important goals of prevention as well as both early recognition and timely therapy of reinfarction.
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Acknowledgments
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The ASSENT-2 trial was funded by Genentech, Inc, and Boehringer-Ingelheim. The authors acknowledge the contributions of ECG readers in the ECG Core Laboratories at the Canadian VIGOUR Centre (Edmonton) and at the Canadian Heart Research Centre (Toronto): Asmatullah Naebkhill, Alina Georgescu, Quamrul Hassan, as well as the editorial assistance of Lynne Calder.
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