Outcomes Worse for STEMI Patients Without Obvious Risk Factors

STEMI commonly occurs in the absence of four common CV risk factors—hypertension, diabetes, hypercholesterolemia, and current smoking—and when it does, outcomes can be worse than those seen in the larger STEMI population, data from the SWEDEHEART registry indicate.

All-cause mortality at 30 days was significantly higher in patients without one of these standard modifiable CV risk factors (11.3% vs 7.9%; HR 1.47; 95% CI 1.37-1.57), dubbed SMuRFs by Gemma Figtree, DPhil (Royal North Shore Hospital, Sydney, Australia), and colleagues.

The disparity was exacerbated in women—SMuRF-less women had the highest rate of 30-day mortality (17.6%), followed by women with traditional risk factors (11.1%). Mortality risks were lower in men, with a smaller difference between those who didn’t versus did have SMuRFs (9.3% vs 6.1%).

The poorer outcomes in SMuRF-less patients were seen over the longer term as well, and they were only partially explained by less use of established therapies for secondary prevention in that group.

The investigators outline the results in a paper published online March 9, 2021, ahead of print in the Lancet.

Figtree told TCTMD that her team hopes to raise awareness about this subset of STEMI patients so researchers can get a better grasp on the underlying biological processes at play and explore the impact of standard post-MI therapies in this group.

“For the moment, definitely all patients who’ve suffered an acute coronary syndrome we know benefit from the standard regimen of secondary-prevention agents, and our study certainly highlights the fact that the lower rates of getting these seems to be contributing to the heightened susceptibility for death,” she said. This group is “being underserved at the moment in terms of appropriate secondary prevention as far as we know,” Figtree said, adding that “just because you appear to be at low risk for getting coronary artery disease doesn’t mean that you’re actually low risk [after having an MI]. In fact, it means that you’re at high risk post heart attack.”

Exploring STEMI Without SMuRFs

This subset of STEMI patients without SMuRFs has not been extensively studied, with Figtree et al noting that publications of clinical trial results tend to report the proportion of patients with various risk factors but not the percentage with none. “Because they’re such a relatively small proportion of the pie, they tend to get left out of subanalyses of large clinical trials, and we really don’t actually have good clinical pathways for these individuals,” Figtree said. “Obviously, secondary-prevention agents are designed for all patients with STEMI, but we don’t actually know whether there’s as much or possibly more benefit from these.”

In a prior study conducted at their center in Sydney, the investigators showed that the proportion of SMuRF-less STEMI increased from 10.9% to 27.4% between 2006 and 2014. A subsequent look at a national Australian registry demonstrated a similar rise and revealed that patients without standard risk factors were more likely to die in the hospital.

To further explore the issue, Figtree and colleagues worked with investigators from the SWEDEHEART registry in Sweden. Their analysis included 62,048 adults who had a first STEMI between January 1, 2005, and May 25, 2018, and did not have a known history of CAD—14.9% had not been diagnosed with any of the four SMuRFs, with a higher rate in women versus men (17.0% vs 10.6%).

Just because you appear to be at low risk for getting coronary artery disease doesn’t mean that you’re actually low risk. Gemma Figtree

The most common SMuRF was hypertension (70.4%), followed by hypercholesterolemia (48.4%), current smoking (32.6%), and diabetes (21.3%). SMuRF-less patients were as likely as those with risk factors to be treated with primary PCI or thrombolysis, but they were less likely to receive statins, ACE inhibitors/ARBs, or beta-blockers at discharge.

The primary outcome was all-cause mortality at 30 days, and the elevated risk in the SMuRF-less group remained even after adjusting for age, sex, LVEF, creatinine, and blood pressure. Accounting for differences in the prescription of therapies for secondary prevention at discharge partially attenuated the association.

Among other outcomes, patients without standard risk factors also had higher rates of mortality, cardiogenic shock, and MACE (all-cause death, MI, heart failure, or stroke) in the hospital. Over the longer term, all-cause mortality remained higher in the SMuRF-less cohort for more than 8 years in men and up to 12 years (the end of follow-up) in women.

Why the Higher Risk Without Risk Factors?

Figtree said the lower rates of prescriptions for secondary prevention therapies at discharge in the SMuRF-less group offer only a partial explanation for the greater mortality risk. She noted that MI and heart failure rates in the first 30 days were not higher in the SMuRF-less group and thus could not have been driving the difference.

Asked to speculate about other potential reasons, Figtree noted that inflammation and oxidative stress are known to play a large role downstream of traditional risk factors, although it’s unknown what impact they have after an MI. “But that might be one hypothesis that might contribute to the sudden death that seems to be driving the mortality in these individuals,” she said.

Commenting for TCTMD, Jeffrey Michel, MD (Baylor Scott & White Health, Temple, TX), said the higher risk in SMuRF-less patients is hard to understand. It’s possible that selecting patients who don’t have one of these standard risk factors is identifying those having an MI that doesn’t stem from traditional atherosclerotic processes but instead is related to a problem with the blood vessels, for instance. He said, too, that hypercoagulable states can result in STEMI through thromboembolic mechanisms independent of atherosclerotic burden.

Therefore, using the established therapies geared toward atherosclerosis may not be as beneficial in this group, Michel said. “You’re treating the heart attack in the moment, but you may not be able to treat the underlying disease process the way we do for atherosclerosis when you’re dealing with some of these nonatherosclerotic processes.”

Figtree said Michel’s point about SMuRF-less patients possibly having MIs not related to traditional atherosclerotic processes is an important one, but added, “In all three studies where we have looked at this, we have been careful to separate out this possibility.”

In their initial study from 2017, “we confirmed all events to be atherosclerotic in origin by review of the angiograms,” Figtree said. “In the large SWEDEHEART study, culprit lesions were identified, and we saw similar rates of primary PCI, similar but slightly less multivessel disease, and lower rates of atrial fibrillation as a cause of potential embolic events. Whilst we did see a higher proportion of spontaneous coronary artery dissection in the SMuRF-less individuals, this was still very low compared to overall STEMI presentations in both groups, and [these patients] actually had a lower 30-day mortality than their sex- and SMuRF-less matched counterparts.”

‘Need to Make Inroads’

Michel said there are certainly patients in his practice who present with STEMI in the absence of traditional CV risk factors, although he said he suspects the proportion is lower in the United States than what was seen in this study.

When it comes to treating them, the standard approach is to provide the same guideline-recommended care other STEMI patients would receive, he said. “There may be some patients who don’t necessarily benefit from all the therapies, but it’s so hard to know that in advance,” he said. “When we err, we’d rather err on the side of treating everybody with medications that at least in large populations have been shown to be beneficial, knowing that within any population there may be some people who don’t benefit from what works for most people. That’s just the nature of practicing medicine.”

If a patient goes to the cath lab and doesn’t have what looks like a traditional STEMI, Michel said he’d dig deeper to find out whether there’s another disease process at play. However, “in the absence of a clear diagnosis, we’ll give guideline-directed medical therapy,” he added.

Figtree said her group is reviewing previous trial data to try to better understand outcomes and the effect of standard therapies in SMuRF-less patients. When considering how many patients die of CAD every year, the number who don’t have these standard CV risk factors—though a minority—is massive, she pointed out.

“We need to make inroads into this group in terms of better early diagnosis of coronary artery disease beyond traditional algorithms,” Figtree said. “We need to be making sure that we understand the outcomes and benefits of particular therapies in this group, and thinking about subgroup inclusion in clinical trials.”

Patients can sometimes feel “embarrassed” for having had a heart attack in the absence of expected risk factors, she said. “We need to make sure that individual susceptibility is something that we continue to try to solve and make sure that over the next decade we can make great progress in tackling the world’s biggest killer.”

In an accompanying editorial, Mai Tone Lønnebakken, MD, PhD (University of Bergen, Norway), highlights the need for better risk stratification among STEMI patients.

“Without consideration of risk, there cannot be gain, and thus new sex-specific risk factors and risk markers should be implemented in clinical risk models that can identify high-risk individuals among SMuRF-less patients with STEMI,” she writes. “Improvement in risk stratification and accurate diagnosis would help to tailor treatment in SMuRF-less patients, reducing the excess mortality and avoiding undertreatment in this subgroup.”