Safety of Routine Invasive Versus Selective Invasive Therapy in Women with Non-ST-Elevation Acute Coronary Syndrome

The efficacy and safety of routine invasive versus selective invasive therapy may not apply similarly to women and men with non-ST-elevation acute coronary syndrome (NSTE-ACS). Meta-analyses have documented a reduction in death or myocardial infarction among NSTE-ACS men that undergo routine invasive therapy [1, 2]. However, benefit has been more difficult to detect among NSTE-ACS women who undergo routine invasive therapy. In addition to bleeding differences [3], women appear to be more likely to present with normal or less severe coronary artery disease [4, 5]. The only randomized trial conducted exclusively in women comparing both approaches documented a non-significant increase in death or myocardial infarction among invasively treated women. In fact, invasive therapy was associated with excess mortality at 1 year [6]. In that study, the risk of major bleeding was approximately 9% at 30 days in the routine invasive arm. The patients were treated with either low molecular weight heparin or fondaparinux, which could have contributed to the increased bleeding [7, 8]. The aim of this study was to compare the safety of routine invasive versus conservative strategies in women who are treated with contemporary medical therapy for NSTE-ACS and to determine the adequate sample size for a randomized clinical trial should this approach appear to be safe.

The study protocol was approved by the University of Florida Institutional Review Board. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

Women who provided written informed consent were randomly assigned to a routine invasive versus a selective invasive strategy. Treatment assignment was performed by opening a sealed opaque envelope. The routine invasive group was recommended to undergo coronary angiography within 48 h of hospital admission. Cardiac catheterization was recommended in the selective invasive group for refractory chest pain, hemodynamic/electrical instability, left ventricular systolic dysfunction, or an abnormal myocardial perfusion stress test; however, patient management decisions were ultimately left to treating physician.

The primary outcome was the risk of major bleeding. Major bleeding was defined as significantly disabling intra-cranial or intra-ocular bleeding, bleeding that required intervention or transfusion, or at least 5 g/dL drop in hemoglobin. The secondary outcome was the first occurrence of all-cause death, myocardial infarction, stroke, re-hospitalization for ACS, or major bleeding within 6 months. Myocardial infarction was defined as an elevation in creatine kinase-MB isoenzyme greater than the upper limit of normal which occurred spontaneously or in the setting of percutaneous coronary intervention. Myocardial infarction in the setting of coronary artery bypass grafting required the presence of new Q-waves [9, 10]. Urgent hospitalization was defined as the need for hospitalization due to an ACS (ST-elevation, non-ST-elevation, or unstable angina) regardless of the treatment delivered (e.g., urgent revascularization versus conservative therapy). Stroke was defined as an ischemic event that caused disabling neurological symptoms that are present for more than 24 h. Urgent target vessel revascularization was defined as recurrent ischemic symptoms that resulted in the need for repeat percutaneous intervention or surgical revascularization. Risk ratio (RR) with 95% confidence interval (CI) for the outcomes was reported. Survival analyses were performed using the Kaplan–Meier method, and the log-rank test was used to compare differences of event-free survival between the two arms. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA).

Twenty-three women were assigned to routine invasive therapy and 17 to selective invasive therapy. All women had 6-month follow-up (24 women followed to 12 months and 13 women to 24 months). Figure 1 summarizes the study flow diagram. Women were 60 ± 13 years of age, 25% had diabetes, 43% were current smokers, and 68% had a history of hypertension (Table 1). The majority of women received aspirin (98%), beta blockers (88%), and statins (80%). Twenty-seven women (68%) had elevated troponin T (mean 0.33 ng/mL) and/or creatinine kinase-MB (mean 23 ng/mL).

One woman randomized to routine invasive therapy subsequently refused catheterization. In this group, the mean time from randomization to catheterization was 11.7 ± 23.2 h. In the routine invasive group, three women underwent successful percutaneous coronary intervention, while in three women a chronic occlusion was unable to be re-vascularized. In the selective invasive strategy group, catheterization was performed for electrical/hemodynamic instability (n = 4), low ejection fraction (n = 3), abnormal stress test (n = 2), and refractory chest pain (n = 1). In the selective invasive group, two women underwent successful percutaneous coronary intervention. Except for one patient in the routine invasive group, catheterization was exclusively performed by femoral artery access.

Only one patient in the routine invasive therapy encountered major bleeding. At 6 months, the composite outcome (intention-to-treat) occurred in 9% of the routine invasive group versus 18% of the selective invasive group (RR = 0.49, 95% CI 0.09–2.63, P = 0.63). Additional outcomes are provided in Table 2. At a mean follow-up of 12.5 months, there was a non-significant benefit favoring routine invasive therapy (log-rank P = 0.11).

Among women with NSTE-ACS, a routine invasive therapy appeared to be safe with no signal for an increase in major bleeding. Although not powered for clinical outcomes, there were numerically fewer adverse cardiovascular events among the routine invasive therapy group. The control arm of our study received selective invasive therapy, which is distinct from conservative therapy. Accordingly, patients underwent monitoring and additional risk stratification during their hospitalization. As a result, many patients crossed over to invasive therapy. However, we do not consider these crossovers to be a limitation, but rather a reality of clinical care.

Although prior meta-analyses had demonstrated the benefits of a routine invasive approach [11, 12], it is important to emphasis that NSTE-ACS clinical trials have shown a remarkable degree of sex bias. In a pooled analysis of ACS trials, women comprised only 25% of the patient population [13]. Furthermore, evidence had shown that bleeding events are higher in women undergoing percutaneous coronary interventions compared with men [14, 15]. Therefore, this pilot study aimed to address the question whether a routine invasive approach would be safe. Although the OASIS-5 sub-study had addressed this same question, the bleeding events in that study were remarkably high which could have been attributed to the study design [6].

Although we attempted to enroll high-risk women, the proportion of women who underwent revascularization was low (i.e., <20%). Approximately one-fifth of women had a chronic total occlusion, which is similar to previous findings [16]. While 68% of our study participants were eligible due to elevated cardiac enzymes, the remainder met other eligibility characteristics which might not adequately risk-stratified patients. However, the median TIMI risk score was 3 and in the TACTICS-TIMI 18 trial, intermediate- to high-risk patients (score ≥ 3) benefited from invasive therapy [17]. Current guidelines recommend routine invasive therapy for high-risk women (i.e., elevated troponin); however, routine invasive therapy is less favorable in low-risk NSTE-ACS women [18]. Based on our observed 6-month event rate of 18% in the selective invasive arm, we estimate that 3454 patients would be needed to detect a 20% relative difference between treatment arms with 80% power.

This study demonstrates that a routine invasive approach is safe in women. There was suggestion of benefit from routine invasive therapy compared with selective invasive therapy. These data could be used to design an appropriately powered trial to determine the optimal management strategy among women with NSTE-ACS.