Meta-analysis: Patient Sex Affects Response to Routine Invasive Approach for NSTE-ACS

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A routine invasive strategy—relative to a more selective approach—appears beneficial over the long term for men but not women with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), according to a study published online July 15, 2014, ahead of print in the American Heart Journal. The difference, however, might be explained by the lesser severity of coronary disease seen in female patients, the authors say.

Joakim Alfredsson, MD, PhD, of Linköping University (Linköping, Sweden), and colleagues looked at pooled data from the FIR database, which includes patients from the FRISC II, ICTUS, and RITA 3  randomized trials. They compared a routine invasive strategy (n = 2,721)—early coronary angiography followed by PCI or CABG if feasible—with a more selective approach (n = 2,746) of initial stabilization with medical therapy plus an invasive procedure for patients with symptoms of ischemia despite treatment, hemodynamic instability, or signs of ischemia on a stress test.
Women made up about one-third of the overall cohort (n = 1,751) and were older on average, less likely to be smokers, and more likely to have a history of hypertension than men. Men were more likely to have a history of MI and revascularization.


Women Miss Out on Benefits of Routine Strategy

After 5 years of follow-up, the routine approach reduced the risk of cardiovascular death or MI (primary endpoint) and its individual components in men but not women (P = .01 for interaction for all; table 1).

Table 1. Five-Year Outcomes by Sex




Adjusted HR (95% CI)


    CV Death or MI

    CV Death











0.73 (0.63-0.86)

0.71 (0.56-0.89)

0.69 (0.57-0.83)


    CV Death or MI

    CV Death











1.05 (0.83-1.34)

0.97 (0.68-1.39)

1.13 (0.85-1.50)


 In an analysis stratified by risk level, men at medium and high risk showed improved outcomes with the routine approach, but women across all risk groups had similar outcomes regardless of treatment strategy.

“Subgroup analyses, especially post hoc analyses, have to be interpreted with great caution, and it has to be emphasized that even in this larger dataset the number of events in women [was] low, [and] the observed difference between men and women could be a matter of lack of statistical power in women,” the authors note. “However, the lower confidence interval indicates, at best, a modest benefit in women.”

Disease Severity a Possible Explanation

Among the patients randomized to a routine invasive strategy, women had less severe coronary disease, which is consistent with prior studies of NSTE-ACS. Women were more likely than men to lack significant stenosis (28.2% vs 9.3%) and less likely to have 3-vessel disease (21.1% vs 30.6%).

“Less severe coronary disease could potentially attenuate the benefit with [a routine invasive] strategy. [This] notion is supported by the fact that the large number of women without any significant stenosis in [that group] had an excellent prognosis, with an event rate of 3.4% of the primary outcome,” the authors explain. “Less severity of epicardial coronary disease in women may indicate that women, in spite of clinical presentation and symptoms suggestive of NSTE-ACS, have a different pathophysiology, affecting benefit from [a routine invasive] strategy.”

Differing Recommendations by Sex?

Practice guidelines recommend a routine invasive strategy for all high-risk patients with NSTE-ACS, but this and other studies have raised the possibility of a sex-based difference in the efficacy of the approach.

“One could argue that these findings should have [an] impact on gender-specific revascularization recommendations in patients with NSTE-ACS,” according to Dr. Alfredsson and colleagues.

But, they add, “Women did have less severe coronary artery disease, and it is reasonable to believe that patients with fewer stenoses [derive] less benefit from [a routine invasive] strategy. Whether there are differences between men and women with similar degrees of coronary disease in benefit from [the] strategy is not known, since no study has randomized patients after coronary angiography.”

Future studies should focus on “[clarifying] differences between the [sexes] in pathophysiology in NSTE-ACS and [finding] the optimal treatment strategy for both women and men according to degree of coronary disease,” they write.



Alfredsson J, Clayton T, Damman P, et al. Impact of an invasive strategy on five years outcome in men and women with non-ST-elevation acute coronary syndromes. Am Heart J. 2014;Epub ahead of print.

  •  Dr. Alfredsson reports receiving lecture fees from AstraZeneca, Merck Sharp & Dohme, and Sanofi-Aventis and serving on the advisory boards of Bristol-Myers Squibb/Sanofi-Aventis and Eli Lilly.

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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The meta-analysis was conducted using resources from the host institutions for the respective studies and from the London School of Hygiene and Tropical Medicine.