a Medical Statistics Unit, London School of Hygiene & Tropical Medicine, London, UK
b Department of Cardiology, Nottingham City Hospital, Nottingham, UK
c National Heart and Lung Institute, Imperial College London, London, UK
d Department of Cardiology, Western General Hospital, Edinburgh, UK
e Department of Medical and Radiological Sciences, Royal Infirmary, Edinburgh, UK
Received April 9, 2004; revised July 14, 2004; accepted July 27, 2004 * Corresponding author. Tel.: +20 7927 2640; fax: +20 7637 2853 (E-mail: tim.clayton{at}lshtm.ac.uk).
See page 1559 for the editorial comment on this article (doi:10.1016/j.ehj.2004.07.002).
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Abstract |
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METHODS AND RESULTS: In total, 1810 patients (682 women and 1128 men) were randomized. The risk factor profile of women at presentation was markedly different to men. There was evidence that men benefited more from an early intervention strategy for death or non-fatal myocardial infarction at 1 year (adjusted odds ratios 0.63, 95% confidence interval 0.410.98 for men and 1.79, 95% confidence interval 0.953.35 for women; interaction p-value=0.007). Men who underwent the assigned angiogram were more likely to be put forward for coronary artery bypass surgery, even after allowing for differences in disease severity.
CONCLUSION: An early intervention strategy resulted in a beneficial effect in men which was not seen in women although caution is needed in interpretation. Further research is needed to evaluate why women do not appear to benefit from early intervention and to identify treatments that improve the prognosis of women.
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Introduction |
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In assessing the impact of an early intervention strategy in men and women with unstable coronary disease, the results from two recent clinical trials appear to lead to conflicting conclusions. The FRISC II trial (Fragmin and Revascularisation during Instability in Coronary artery disease II) trial indicated a benefit of early intervention for death or myocardial infarction in men which was not seen in women.24 The TACTICS-TIMI 18 trial (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy Thrombolysis In Myocardial Infarction 18) reported a benefit of early intervention for death, myocardial infarction or re-hospitalisation that was seen in both men and women.25 In addition, a recent observational study in patients with non-ST-elevation acute coronary syndromes assessing the impact of very early intervention reported a better long-term outcome of death or myocardial infarction in women compared to men.26 The impact of gender on the treatment and outcome of patients with non-ST-elevation myocardial infarction or unstable angina therefore remains uncertain and RITA 3 (Randomized Intervention Trial of unstable Angina) provides the opportunity for further insight as to whether such gender differences exist.
The results from the RITA 3 trial indicated that patients benefited from an early intervention strategy in comparison to a conservative strategy largely due to a reduction in the incidence of refractory angina.27 A subgroup analysis suggested that men benefited from a strategy of early intervention in terms of the primary outcomes of (i) death, myocardial infarction or refractory angina at 4 months, and (ii) death or myocardial infarction at 1 year, whereas no such benefit was seen in women. In this paper we test the hypothesis that the differences in the benefit of early intervention between women and men are due to differences in the baseline clinical characteristics and disease severity. In addition, differences in the management of men and women randomized to early intervention will be explored.
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Methods |
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It was intended that patients randomized to the intervention group underwent coronary angiography within 72 h of randomization. Patients randomized in centres without on-site angiographic facilities were transferred to an intervention centre. The need for revascularization in those undergoing early angiography was determined by the clinician responsible. The protocol recommended revascularization in major epicardial vessels with ⩾70% diameter stenosis (⩾50% for left main stem).
Patients randomized to the conservative treatment strategy were managed with antianginal and antithrombotic medication with the objective of providing the best medical treatment available at the time of randomization. Coronary angiography could be undertaken for failure of the conservative treatment strategy. During the index admission this constituted at least one of (i) recurrence of ischaemic pain at rest or on minimal exertion, with transient or persistent electrographic evidence of ischaemia despite full antianginal medication, or (ii) the inability to withdraw intravenous antianginal or antithrombotic medication without recurrence of ischaemic chest pain. Following discharge from the index hospital admission, failure of the conservative treatment strategy included exertional angina despite optimal antianginal medication.
Patients were seen at 4 months and 1 year, and follow-up is to be maintained annually to 5 years following randomization.
Q-wave myocardial infarction was diagnosed when new Q-waves were detected on a follow-up electrocardiogram when compared with the baseline electrocardiogram. Other myocardial infarctions were diagnosed when a clinical event was accompanied by electrographic evidence of acute myocardial infarction associated with a rise in at least one cardiac enzyme to twice the upper limit of normal. In patients for whom baseline levels of enzymes were already raised, a further twofold increase beyond the first 24 h following randomization was required.
Refractory angina was diagnosed during the index admission if recurrence of chest pain was associated with electrographic evidence of myocardial ischaemia, and led to a revascularization procedure within 24 h of the onset of pain. Following discharge from the index hospital admission, refractory angina was diagnosed if the patient was readmitted with an episode of cardiac chest pain associated with electrographic evidence of myocardial ischaemia. Episodes of refractory angina occurring up to 1 year after randomization were reported.
All patients provided written informed consent and RITA 3 complies with the Declaration of Helsinki.
Statistical methods
All analyses were performed by intention to treat except for analyses based on patients who underwent randomized coronary arteriography. Differences in baseline characteristics and disease severity between women and men were compared with t-tests and 2 tests. The main outcome considered was death or non-fatal myocardial infarction at 1 year, with further analyses investigating death or non-fatal myocardial infarction over all available follow-up at the date the last randomized patient had been in the trial for 1 year. Logistic regression was used to examine gender differences in outcomes at 1 year (including interaction tests) and results are presented as odds ratios together with 95% confidence intervals (CI). Adjustment was made for baseline characteristics that were independently associated with the outcome (from a forward stepwise procedure). Cox regression was used for evaluating effects of gender and treatment on the outcome of death or non-fatal myocardial infarction over follow-up beyond 1 year and KaplanMeier graphs are presented for women and men separately.
In addition the outcomes of death alone and death, myocardial infarction or refractory angina at 1 year were also considered. In assessing the impact of disease severity on planned revascularization procedures among patients randomized to the intervention arm, cross-tabulations were made of the proposed management plan by disease severity in men and women separately. Men and women were also stratified according to risk on the basis of available factors included in the TIMI risk score20 to assess whether these characteristics explained any gender differences. Finally, the benefits and hazards of intervention were investigated in men and women separately according to their body mass index levels.
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Results |
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The impact of gender on the primary outcome
For the primary outcome of death or non-fatal myocardial infarction at 1 year there was evidence that the effect of an early intervention strategy compared to a conservative strategy differed between men and women (Table 4). There were 38 (7.0%) men in the intervention arm experiencing death or myocardial infarction by 1 year compared to 59 (10.1%) men in the conservative arm, whereas among women 30 (8.6%) in the intervention arm compared to 17 (5.1%) in the conservative arm experienced this outcome (unadjusted interaction p-value=0.011). In order to consider the impact of the baseline characteristics of patients, a multivariable analysis was conducted. Factors independently associated with an increased risk of the outcome were age, ST depression (⩾0.1 mV), heart rate, previous myocardial infarction, diabetes and severe angina. After adjustment for these factors, the odds ratio for men (intervention vs. conservative) was 0.63 (95% CI 0.410.98) and for women 1.79 (95% CI 0.953.35) (interaction p-value=0.007). In the conservative arm, women had a decreased risk compared to men (adjusted odds ratio 0.39, 95% CI 0.220.70) whereas in the intervention arm the risks were similar (adjusted odds ratio 1.11, 95% CI 0.661.85). These results were very similar after further adjustment for body mass index.
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There was also an indication of differences in death or myocardial infarction between men and women over the longer term (Fig. 1) with an adjusted hazard ratio for men of 0.61 (95% CI 0.440.85) and for women 1.09 (95% CI 0.701.71) (interaction p-value=0.042). The KaplanMeier curves display the observed treatment differences for death or myocardial infarction for all available follow-up at the date the last patient randomized had been in the trial for 1 year, and show the apparent benefit of intervention in men which is not seen in women.
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The effect of treatment was examined in men and women separately for each category to explore whether this accounted for the observed gender differences. For both men and women there was an increase in the event rates for each increase in the risk score (from 5.6% to 14.4% in men, and from 3.0% to 10.0% in women). In those with lower risk the event rates were very similar in the intervention and conservative arms for both men (6.1% vs. 5.1%) and women (2.3% vs. 3.8%). However in men with moderate and higher risk scores, those in the intervention arm had a lower event rate than those in the conservative arm (5.4% vs. 9.5% and 10.3% vs. 17.9% in the moderate and higher risk groups respectively), whereas women in the intervention arm had higher rates (13.4% vs. 3.4% and 11.7% vs. 8.2% in the two risk groups respectively). The results indicate that in men the benefit of intervention was in patients at moderate or higher risk, whereas this pattern was not observed in women where no benefit was seen even in the higher risk patients.
The effect of the randomized intervention was examined by body mass index group (with cut-offs at 25 and 30 kg/m2) in men and women separately. The results suggested any benefit of intervention in men was consistent across all body mass index groups with no benefit of intervention seen in any body mass index group for women.
The timing of outcome events
Among men, the event rate of death or myocardial infarction in the first 7 days following randomization was similar in the 2 treatment groups (3.44 per 1000 days in the intervention arm compared to 3.73 per 1000 days in the conservative arm), whereas after the first 7 days the event rate is consistently lower in the intervention arm. Eight of the 13 events in the first 7 days occurring among men in the intervention arm were related to the randomized angiogram or assigned PCI. Two of the 15 events by 7 days occurring among men in the conservative arm were related to a PCI. Among women the event rate in the first 7 days was increased in the intervention arm (5.85 per 1000 days) compared to the conservative arm (1.30 per 1000 days), whereas after the first 7 days the rates in the two arms were remarkably similar. Nine of the 14 events in the first 7 days among women in the intervention arm were related to the randomized angiogram or assigned PCI. None of the three events among women in the conservative arm were related to a procedure. There were seven CABG-related deaths in the intervention arm (five men, two women) in the first year of follow-up compared to three CABG-related deaths (all men) and one CABG-related myocardial infarction (in a male) in the conservative arm (Table 5).
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In patients randomized to the intervention group, 19 (36%) women with three-vessel disease were treated medically compared to 24 men (18%). Among these, patients five women and five men experienced an outcome of death or myocardial infarction by 1 year (nine of these 10 patients died within a year of randomization). None of these 10 patients underwent a revascularization procedure.
Thus the difference in the effects of the randomized treatment strategies between men and women reflects, in part, a low early event rate in women in the conservative arm, and a high early event rate in the interventional arm that cannot fully be explained by events related to revascularization procedures. Further, the differences in the event rates between men and women in the intervention arm were enhanced after excluding those with no significant disease. At 1 year in patients with one, two and three significantly diseased vessels there were 8 (4.5%), 13 (8.8%), and 15 (11.2%) men respectively who died or had a myocardial infarction compared to 7 (6.8%), 9 (15%), and 10 (18.9%) women.
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Discussion |
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Disease severity
It has been suggested that the benefit of early intervention in patients with unstable angina or non-ST-elevation myocardial infarction is greatest in those with more severe coronary disease,25 whereas women in RITA 3 may represent a particularly low risk group. A strategy of early intervention will identify those with more severe disease earlier than a conservative approach, and these patients may benefit from early revascularization. In RITA 3, a patient could be randomized if the participating cardiologist was satisfied that either strategy was an acceptable option and as a result the patients in RITA 3 had a lower risk profile than in earlier trials. In RITA 3 women presented with worse symptoms than men but after adjustment for baseline risk factors, gender differences in outcomes remained. In addition, there were no significant differences between men and women in the TIMI risk score based on the risk factors available. This did not change after the inclusion of ⩾50% diameter stenosis as an additional component among patients in the intervention arm. In contrast to men, women in the moderate and higher risk TIMI groups showed no benefit of an early intervention.
It has been suggested recently that men and women with unstable angina or non-ST-elevation myocardial infarction have different levels of biomarkers at presentation, and that marker-positive women had improved outcomes with early intervention, whereas marker-negative women had improved outcomes with a conservative strategy.28 In RITA 3, men presented with raised levels of creatinine kinase more often than women although the overall number of patients with raised levels was low.
Complications from revascularization procedures
Women may experience more complications from invasive treatment. Previous studies have reported that target vessel size (or measures of body size used as a surrogate) help to explain the differences in outcomes between women and men following CABG or PCI,4,29 although a recent study combining data from five trials and one registry reported that a small target vessel did not account for the higher mortality seen in women following PCI.7 In RITA 3, body mass index (used as a surrogate for vessel size) did not explain the apparent gender differences with men showing a consistent benefit from intervention across all body mass index groups and no benefit was seen in women in any group. Although based on a fairly small number of events, there is a suggestion that some, but not all, of the excess risk in women randomized to early intervention relates to an increased procedure-related risk in the first week together with a low event rate in the conservative arm. However, after excluding events within 3 days of a revascularization procedure, an early excess risk among women in the intervention arm was still apparent.
Referral bias
In patients with comparable disease severity, there may be a gender bias in referral for angiography, PCI or CABG. Having adjusted for the number of significantly diseased vessels there was an indication that men with two- and three-vessel disease were more likely than women to be put forward for CABG (52% vs. 36%), whereas for PCI there was little evidence of a difference (28% vs. 34%). This may represent a less aggressive approach for treating women, particularly women with small coronary arteries. Women with two- or three-vessel disease may more commonly represent a particularly high risk group of patients with small coronary arteries. Among the patients with two- or three- vessel disease, 34 women (30%) were treated medically compared to 56 men (20%). Of these patients, seven women (21%) experienced the primary outcome compared to six men (11%).
Limitations and comparison with other trials
The results may have arisen by chance (or at least be an exaggeration of the true impact of gender on the effect of early intervention). Caution is needed in the interpretation of any differences arising from subgroup findings especially as trials are rarely powered for such analyses.30 In addition, detailed analyses of the possible explanations for the differences observed are post hoc and limited by the low numbers. One explanation of the lack of benefit of early intervention in women could be the very low event rate observed in the conservative group, possibly due to a high proportion of women in this group with normal or near normal coronaries. However, there are several factors which suggest that gender differences may exist in this population of patients. The interaction between gender and treatment was one of only five subgroup analyses undertaken for the primary endpoint of death or myocardial infarction within 1 year of randomization.27 Moreover, we found a gender difference for death alone, and also with the inclusion of refractory angina to the primary outcome. In addition there was some evidence that men benefited more from early intervention in terms of any symptoms of angina at 1 year (interaction p-value=0.027) but not in terms of severe symptoms (interaction p-value=0.23).
In addition, the results are consistent with those of FRISC II which also observed a benefit of early intervention on death or myocardial infarction in men alone. While TACTICS-TIMI-18 demonstrated a benefit of early intervention in both men and women, there are possible explanations for the differences seen with RITA 3 and FRISC II. In TACTICS-TIMI-18, by design, patients were routinely treated with a glycoprotein IIb/IIIa and this is suggested as a reason for the improved outcome among women receiving invasive therapy. 25 However, there is some uncertainty as to the benefit of routine treatment with glycoprotein IIb/IIIa in women with non-ST-elevation acute coronary syndromes (particularly in those without raised troponin concentrations)31 and alternative reasons for the differences between the TACTICS-TIMI-18 trial, and the RITA 3 and FRISC II trials have been suggested;32 for example, differences in the procedural risks and risk profiles of enrolled patients. There may also be other differences in the clinical practice of patients with unstable angina or non-ST-elevation myocardial infarction in the US compared to the UK and Scandinavia.
A further determinant of the impact of early intervention is in the definition of a procedure-related myocardial infarction. In RITA 3, a consistent definition for both procedure and non-procedure related infarctions was used, whereas both FRISC II and TACTICS-TIMI-18 used more stringent definitions of myocardial infarction following a revascularization procedure. Furthermore, a conservatively treated patient in TACTICS-TIMI-18 was defined as having sustained a myocardial infarction with any increase in enzyme or marker concentration above the normal diagnostic limit for normal controls, compared to FRISC II where usually a twofold increase was required. Thus, the beneficial effect of early intervention observed in women in TACTICS-TIMI-18 may, in part, be influenced by the definition of myocardial infarction used. An additional analysis presented in the main RITA 3 paper indicated that significant differences between the groups would be observed by using the ESC/ACC criteria of myocardial infarction largely as a result of the lower threshold for diagnosis of myocardial infarction among the conservatively treated group. We repeated the subgroup analysis of death or myocardial infarction using these criteria to assess whether this might explain differences seen between RITA 3 and TACTICS-TIMI-18. At 1 year, 73 (13.4%) men in the intervention group and 114 (19.6%) in the conservative group would have met the criteria for death or myocardial infarction using these criteria, and for women the numbers were 39 (11.1%) and 42 (12.7%), respectively (interaction p-value 0.24). Thus, these data support the hypothesis that some of the observed differences between the trials may be due to the definitions of myocardial infarction used.
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Conclusions |
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Acknowledgments |
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For a complete list of investigators, committee members and participating centres please refer to Lancet 2002;360:750.
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References |
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