Division of Cardiology, Department of Medicine, The Henry Low Heart Center at Hartford Hospital, Hartford, CT, USA
The University of Connecticut School of Medicine, Farmington, CT, USA
* Correspondence to: William E. Boden, MD, Division of Cardiology, Department of Medicine, The Henry Low Heart Center at Hartford Hospital, Room JB-722, 80 Seymour Street, Hartford, CT, USA (E-mail: wboden{at}harthosp.org).
This editorial refers to "Do men benefit more than women from
an interventional strategy in patients with unstable angina or
non-ST-elevation myocardial infarction? The impact of gender in the
RITA 3 trial". by T.C. Clayton on
page 1641
Coronary artery disease and, in particular, acute coronary syndromes (ACS), is the leading cause of mortality and morbidity in industrialised nations.1 While major advances in the diagnosis and treatment of ACS, both in terms of pharmacotherapy and catheter-based revascularisation, have resulted in a continuing, steady decrease in coronary heart disease (CHD) mortality over the last decade among men, the cardiovascular event rate among women has either levelled off or increased especially in older age groups and among various ethnic minorities.24
One of these advances, percutaneous coronary intervention (PCI), has become a standard treatment option for many patients both men and women with CHD, and has become increasingly widespread in North America and Europe as the dominant management strategy in patients who present with ACS. Among ACS patients who exhibit ST-segment elevation myocardial infarction (STEMI), the benefits associated with primary PCI are unquestioned, with significant improvements in survival and myocardial salvage as a consequence of the more rapid and complete restoration of antegrade coronary flow through an infarct artery. However, for patients who present with non-ST-segment elevation (NSTE) ACS, the overall benefits associated with an early interventional strategy are more heterogeneous, with clear benefits apparent in high-risk ACS patients, particularly those with biomarker positivity and/or ST-segment depression, and a more neutral effect, compared to a non-invasive, or "ischaemia-guided" management approach, in low-risk patients.5
Even among intermediate- and high-risk ACS patients, however, there is controversy regarding the putative benefits of the early invasive strategy in women, compared to men. Indeed, randomised controlled trials comparing the benefit of an early invasive strategy in NSTE ACS have yielded disparate and often conflicting results with the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction-18 (TACTICS TIMI-18) Trial suggesting clear benefit of an early invasive approach without regard to sex6 and the Fragmin and Revascularization during Instability in Coronary artery disease II (FRISC-II) Trial, demonstrating that all of the benefit observed in ACS patients who received the early invasive strategy occurred in men.7
In this issue of the European Heart Journal, Clayton and colleagues report a critically important post hoc analysis from the RITA-3 (Randomized Intervention Trial of unstable Angina-3) study that supports a similar analysis in FRISC-II, namely, that an early invasive strategy resulted in a beneficial effect in men that was not seen in women.8
In RITA-3, 1840 patients with NSTE ACS were randomly assigned, within 48 hours of the index event, to receive either an interventional strategy (routine coronary angiography, PCI, or coronary artery bypass graft [CAGB] surgery) or a conservative strategy (medical therapy, with revascularisation reserved for patients with inducible or spontaneous ischaemia). One third of the participants were women; they were older than men and had higher rates of dyslipidaemia and more severe angina; they had lower rates of prior myocardial infarction (MI) and troponin levels. Of note, women were also more likely than men to have no significant coronary artery stenoses by angiography compared with men. PCI for ACS management was planned in a similar proportion of men and women, but CABG was planned more for men compared with women.
The RITA-3 gender-specific subgroup analysis revealed that men had a significant reduction in the composite of death and MI at one year with the early intervention strategy compared to women (adjusted odds rates 0.62; 95% confidence intervals 0.410.98 for men; adjusted OR; 1.70; CI 0.95 to 3.35 for women; interaction P value=0.07). For both men and women, there was an increase in the event rates for each increase in the TIMI risk score (from 5.6% to 14.4% in men and from 3.0% to 10% 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%).8
As noted above, these findings essentially replicate the earlier post hoc analysis of the FRISC-II study, but run counter to the observations from the TACTICS-TIMI 18 trial. In the non-invasive group of FRISC-II, women had significantly better outcomes than men. By contrast, in the invasive group, female sex was independently associated with excess death and MI at 12 months, and the intervention between sex and treatment strategy was significant (P=0.008).9 However, in TACTICS-TIMI 18, women who underwent PCI had similar rates of death and MI at 6 months compared with men (10.7% in women undergoing PCI vs. 10.9% in men undergoing PCI, P>0.99). Furthermore, women with elevated levels of troponin had a marked benefit with an invasive strategy (adjusted OR, 0.47; 95% CI, 0.260.83).10
What accounts for these disparate and incongruent results in the RITA-3, FRISC-II, TACTICS-TIMI 18 subgroup analyses? Both RITA-3 and FRISC-II allowed for patients to be enrolled if they had symptoms within 48 hours, while TACTICS-TIMI 18 had more stringent enrolment criteria within 24 h of symptom-onset. These different enrolment strategies may have selected for patients with different risk profiles. In both FRISC-II and RITA-3, women in the conservative strategy group appeared to be at lower risk of death and MI. Hence, procedural risk may become magnified, or increasingly unmasked, in such low-risk patients and proportionately more pivotal in determining the "net clinical benefit" for those assigned to invasive therapy. Another difference between RITA-3 and FRISC-II, on the one hand, and TACTICS TIMI-18, on the other, is the use of platelet glycoprotein (GP) IIb/IIIa receptor antagonists. In FRISC-II, while all patients received dalteparin, only about 10% were receiving concomitant abciximab. Similarly, in RITA-3, unfractionated heparin (UFH) was used as the dominant antithrombin treatment and it is unclear what percentage of women received a GP IIb/IIIa inhibitor, but presumably it was small. Conversely in TACTICS, by trial design, all patients received aspirin, UFH and tirofiban, which may have not only reduced the incidence of early recurrent ischaemic events and MI, but may also have afforded more complete platelet inhibition in ACS patients during PCI. Additionally, in both FRISC-II and RITA-3, there was a longer duration of antecedent medical therapy prior to PCI or CABG (several days), whereas in TACTICS, the majority of ACS patients (60%) underwent PCI within 2 days. Recent data from the ISAR-COOL Trial11 supported better short-term outcomes in ACS patients who underwent very early intervention, compared to more delayed intervention, although it is unclear why the time course of intervention should be gender-specific. Moreover, we know that women who undergo myocardial revascularisation, in general, may fare worse than men, in that women tend to be older, have more cardiac risk factors, more co-morbidities, often a smaller body surface area, and smaller coronary arteries that may not be as amenable to PCI and target vessel revascularisation. Lastly, gender differences in clinical outcomes among the three randomised trials of ACS who underwent an early invasive strategy may simply reflect the statistical play of chance.
The authors correctly state that, "establishing why women may fare less well from an early intervention is not straightforward". Are these differences the results of disparities in the diagnosis and treatment of women with ACS? Is it because women and men respond differently to the same cardiovascular therapies? Are there sex differences in cardiac anatomy, or an interaction between physiologic and anatomic risk factors that place women at increased risk when they undergo early intervention?12 Clearly, more prospective, randomised trials are needed to answer these questions and to further clarify the optimal management strategy for women presenting with NSTE ACS.
In summary, the RITA-3 subgroup analysis raises continued questions about whether the benefits of an early intervention strategy apply equally among women and men with ACS. Although patients in RITA-3 had overall lower risk profiles than in earlier studies, the women in the moderate and higher risk TIMI groups still showed no benefit of an early intervention strategy compared to men. Thus, it remains unclear at present whether the sex differences observed in two of the three major randomised trials of NSTE ACS reflect differential risk profiles of the female patients, the time interval between symptom-onset and intervention, the adjunctive antiplatelet and antithrombin therapies used periprocedurally, or as yet unidentified factors. These data continue to emphasise the need to employ appropriate risk stratification in the management of NSTE ACS patients and to base decisions on the need for early intervention according to the presence of high-risk features that are known from evidence-based trials to improve event-free survival in these patients.
Footnotes
doi:10.1016/j.ehj.2004.07.032.
References
Related articles in EHJ: