CABG Loses Survival Advantage in Women at 10 Years: SYNTAXES

Contrary to what was seen in 5-year follow-up of the SYNTAX trial, gender does not independently predict all-cause mortality at 10 years after revascularization in patients with complex coronary artery disease. The findings support the removal of gender from the SYNTAX II score, the authors say.

At 5 years, women with who received PCI were significantly more likely to die than those who received CABG (adjusted HR 0.38; 95% CI 0.17-0.87), although no such difference was observed in men. Ten-year results of the SYNTAX Extended Survival (SYNTAXES) study, published in the August 25, 2020, issue of the Journal of the American College of Cardiology, now show no difference between treatment options for women (adjusted HR 0.90; 95% CI 0.54-1.51). Interestingly, the survival curves for men began to diverge around 7 years, but this did not reach statistical significance at 10 years (adjusted HR 0.76; 95% CI 0.56-1.02).

Currently in press, the SYNTAX Score 2020 will increase the capacity of operators to perform precision medicine by now including smoking and diabetes and eliminating gender, senior author Patrick Serruys, MD, PhD (National University of Ireland, Galway), told TCTMD. “It is a probabilistic formula, so everybody can use it,” he said, adding that his team is also working on an iPhone app. Ultimately though, “somebody will, again, challenge the surgeon or challenge the interventional cardiologist in the near future because the whole field is continuously moving.”

Commenting on the study for TCTMD, Laxmi Mehta, MD (Ohio State University, Columbus), said despite several caveats—the low proportion of female participants enrolled at the start of the study and outdated stent technology, to name a couple—the findings are helpful, especially for further understanding sex differences. “We need more gender studies; whatever is there just isn't enough,” she said. “The unfortunate part is that we just need more data on women and racial and ethnic diverse groups. That's not even teased out in this manuscript, and so I think that's where we're lacking.”

Converging Curves

For the SYNTAXES study, which will also be presented at the upcoming virtual European Society of Cardiology Congress, Serruys, Hironori Hara, MD (University of Amsterdam, the Netherlands), and colleagues included 10-year follow-up survival data on 93.8% of the original 1,800 patients enrolled in SYNTAX from both the United States and Europe. Notably, female patients, who represented 22.3% of the cohort, were about 4 years older than male patients at baseline (68.1 vs 64.2 years; P < 0.001) and also had a higher prevalence of diabetes, hypertension, and chronic kidney disease as well as higher EuroSCORE values.

While male patients were more likely to present with three-vessel disease, women were more apt to have left main CAD. Men also had slightly higher SYNTAX scores on average (29.2 vs 27.0; P = 0.001) and were more likely to have any total occlusion or bifurcation.

At 10 years, overall all-cause mortality was higher for women than men (32.8% vs 24.7%; P = 0.002). While this was also true for those who received CABG (32.5% vs 22.5%; P = 0.017), there was only a trend for female and male patients who received PCI (33.0% vs 27.0%; P = 0.053). Among women, there was no difference in 10-year all-cause mortality between CABG and PCI (P = 0.601), nor was there any difference between revascularization types among men (P = 0.082).

What Happened Between 5 and 10 Years?

As for what may have happened over the years to make the female curves converge and the male curves start to diverge, Serruys said, “we can only make a hypothesis.” He stressed the difference in baseline age between women and men, and said that life expectancy in general could play a role. “What is puzzling to me is the fact that the curve of the bypass surgery, . . . which was initially better for a female CABG, at the end converges, and that should be related to something surgical,” he said, adding that when the study was conducted, the use of saphenous vein grafts were more prevalent, and their life span is generally about 7 years.

Additionally, Serruys suggested, bypass surgery has been shown to have a cardioprotective effect in three-vessel disease. “If you have a vulnerable plaque in the proximal LAD and you have the internal mammary artery on the LAD, the vulnerable plaque can rupture and nothing happens because you have a bypass on the LAD,” he explained. “But if you have a stent in the middle of the LAD and you get the plaque rupture proximal to the stent, then you are in trouble.”

Mehta agreed that the fact female patients were older at baseline could have affected the final results. “Women tend to be older and they tend to have more of those other comorbidities. And are those comorbidities playing a bigger effect as they get older?” she asked. “The other question is: when you have more of those comorbidities, how much of those are under control? Are they better controlled in the first 5 years and not afterwards? Are they having more interactions as they're getting older with their medications? Is it [being] more lax in the medical community or in the patient community about those other risk factors that are impacting care?”

With so many overlapping risk factors, it’s hard to tease out the culprit, Mehta continued. “The other thing, though, is that they were really looking at mortality rates in this and didn't really look at other factors” like revascularization, unstable angina, and stroke. Also, “even though women have longer lives than men, their healthy quality-of-life years are less, and so we don't have that [either]. . . . It's not just getting someone to live, but it's getting them to live a meaningful life that they want as well. And that also is missing.”

This is where future research should focus as well as on the connection between gender and ethnicity, Mehta said. “When we make decisions, even though this data is there and there are guidelines and there are data, at the end of the day, every patient is so unique and they need personalized decision-making of what's best for them and looking at them as a whole.”

Serruys added that to give more-specific guidance, studies in the future will have to enroll enough women such that they reach at least 50% of participants. “But not even that will not resolve the problem of the difference of baseline characteristics,” he said. “So you will be always dependent on propensity analysis.”

Comorbidities vs Sex

In an accompanying editorial, Arnold Seto, MD (Long Beach VA Hospital, CA), asks: “If CABG is superior to PCI, is it any more so for women than men?” While women who received CABG in this study tended to live longer than those who underwent PCI, and no such observation was seen in men, he points out. “CABG would thus appear to potentially provide a reasonable survival benefit over PCI in women.”

However, since this sex-treatment interaction has not been confirmed in the EXCEL, FREEDOM, BEST, PRECOMBAT, BARI, and MASS studies, he says “the interaction seen in the 5-year SYNTAX results was likely a type 1 error.” The decision to revise the SYNTAX II score to remove female sex “appears warranted” based on these findings, Seto writes.

Notably, he says, “the results of SYNTAXES illustrate how the relevant duration of follow-up may depend upon the population tested. An elderly population of patients > 75 years of age would be more likely to have mortality confounded by competing risks over a 10-year follow up period. In contrast, for a younger patient population (age < 55 years), 15-year or longer follow-up might be more feasible and desirable to fully demonstrate the consequences of graft failure.”

Still, it is important to keep in mind that “long-term mortality tends to be biased towards the null,” Seto adds. “Early mortality may represent relatively rare events that are susceptible to chance and should not be overinterpreted, especially when studying subgroups of the larger population. Other endpoints such as years of life saved, quality-adjusted life-years, and MACE may better capture the benefits of different revascularization decisions, even if they have a higher risk for bias.”

Ultimately, it may be more astute to focus on the comorbidities of a patient rather than sex, he says. “The results of SYNTAXES suggest that after accounting for the delay in onset of coronary disease, men and women may be made more alike than different, especially when it comes to life and death.