Nearly everyone who went on to suffer a heart attack, stroke, or heart failure already had at least one traditional cardiovascular risk factor above the optimal threshold before the event, according to a large study of people in South Korea and the US.

This finding contradicts some recent studies indicating the number of people with cardiovascular disease who did not have any of the standard modifiable risk factors (SMuRFs) was rising. Those data also suggested these “SMuRF-less” patients tend to have worse outcomes than those with traditional risk factors.

This seemed unlikely to Philip Greenland, MD, a cardiologist at Northwestern University in Chicago, given how prevalent these risk factors are in the population.

“It was incomprehensible to us that we could have people without at least some exposure to nonoptimal risk factors,” he told Medscape Medical News.

Greenland and his colleagues looked at the four SMuRFs — blood pressure, cholesterol, glucose levels, and smoking status — and focused on risk factor levels shy of the thresholds for diagnosis but above ideal levels, such as cholesterol above 200 mg/dL vs the clinical threshold of 240 mg/dL for hypercholesterolemia.

The researchers evaluated the health records of more than 9 million people in South Korea and nearly 7000 in the US. They included 601,025 cardiovascular events from the Korean database and 1188 events from the US database in their analysis.

Results showed more than 99% of patients who were diagnosed with coronary heart disease, heart failure, or stroke had evidence of at least one nonoptimal risk factor before the event, with more than 93% having two or more nonoptimal risk factors. The finding was consistent across both countries, types of cardiovascular events, and age subgroups, and was largely consistent between men and women. The presence of clinically elevated risk factors was also high, hovering between 90% and 95%, according to the data. The study was published in the Journal of the American College of Cardiology.

Nonoptimal Levels vs Diagnosis

Greenland said much of the discrepancy between this study and the previous ones looking at SMuRF-less patients is attributable to their focus on patients with a clinical diagnosis of risk factors, like hypertension or hypercholesterolemia, and ignoring those in the gap between optimal and diagnosable. By the time patients receive a diagnosis, they will have had considerably nonoptimal levels for some time, he said.

“Anything above that optimal level is associated with an increasing level of risk,” he said. “There might be some people with a little elevation of blood pressure, cholesterol, or blood sugar, but those little elevations are not trivial.”

Gemma Figtree, MD, a cardiologist at The University of Sydney in Sydney, Australia, who worked on some of the SMuRF-less studies, said the debate largely comes down to definitions, noting that the lower thresholds in the new study, while relevant, are not likely to change how patients are treated.

“The authors have dropped the bar to a level that is currently not pragmatic in the real world and would not lead to widespread pharmacotherapy,” she said.

Looking Beyond Risk Factors

Rather than focus on risk factors, Figtree said her group’s work looks at variation in susceptibility and resilience, and the fact that those who experienced cardiac events despite having a lower risk factor burden have a 50% higher early mortality rate after a heart attack. She said finding better ways of detecting and treating subclinical cardiovascular disease would provide a more intelligent approach than only relying on population-level risk.

“In cancer, if we only focused on risk factors, we would miss the fact that some patients get cancer without those risk factors. Looking for the disease itself is one way we are interested in helping move beyond the debate,” she said.

But Greenland said it is still important for providers to pay attention to the major modifiable risk factors, not least because they are something that patients can do something about.

“We have a tendency to overlook levels that are not quite at the range where drugs will be used,” he said. “But even if you’re not going to write a prescription for someone with a blood pressure of 130 mm Hg, they still qualify for attention. Diet, exercise, and weight management shouldn’t be ignored.”

In an accompanying editorial, Neha J. Pagidipati, MD, MPH, of the Duke Clinical Research Institute in Durham, North Carolina, also highlighted the high prevalence of traditional risk factors in the study as particularly interesting.

“That 90%-95% of individuals with any type of cardiovascular disease had at least one clinically elevated risk factor in two very different national cohorts suggests that prior estimates of SMuRF-less-ness, which relied on clinically diagnosed risk factors, may have underestimated the prevalence of traditional risk factors and consequently overestimated the prevalence of cardiovascular disease without traditional risk factors,” she wrote.

Even so, Pagidipati noted clinicians should not just rely on these factors when focusing on prevention.

“[T]he debate around the presence of risk factors before CVD [cardiovascular disease] highlights the fundamental inadequacy of estimating cardiovascular risk and assigning preventive therapies based on risk factors alone. In our current paradigm, we assess risk with calculators that heavily weight age (leaving most younger adults untreated), rely on traditional risk factors that are routinely underdiagnosed, and ignore nontraditional factors that can increase risk,” she wrote.

Greenland reported no relevant conflicts of interest. Figtree reported receiving personal fees from Amgen, AstraZeneca, Bayer, CSL, and Janssen. Pagidipati reported serving as a consultant or on advisory panels or steering committees for Amgen, Bayer, Boehringer Ingelheim, Corcept, Corsera, Eli Lilly, Esperion, AstraZeneca, Merck, New Amsterdam, Novartis, and Novo Nordisk, and has been on the data and safety monitoring board for trials sponsored by J+J and Novartis.

Brian Owens is a freelance journalist in New Brunswick, Canada.