It’s a math problem with life-and-death consequences.
When a new and improved model for estimating the risk of developing atherosclerotic cardiovascular disease emerged in November 2023, the calculator won raves for drawing on a larger, more contemporary, and more diverse population of Americans than its predecessors. But along with the praise came predictions last year that 40% of U.S. adults might no longer qualify for statins, the widely prescribed pills that fight artery-clogging cholesterol.
Those forecasts acknowledged that the second shoe had yet to drop. Equations come first, to estimate who’s at risk, but thresholds are the next step needed to establish when they might benefit from treatment. The new research concludes that a revised threshold for prescribing based on the improved risk calculator would mean roughly the same number of people qualify for a statin as before.
That’s an important decision when cardiovascular disease, including heart attack and stroke, continues to lead all causes of death. And within that ranking, atherosclerotic cardiovascular disease tops the list for causing preventable deaths and disease in American men and women. Determining a threshold that balances benefit with risk is why medical organizations have yet to issue guidelines based on the new equations. Under the existing recommendations, far fewer people who could benefit from statins actually take them now. Many who start taking them stop.
A research letter published Wednesday in JAMA Cardiology reveals what different thresholds would look like based on the PREVENT model, short for Predicting Risk of Cardiovascular Disease EVENTs, which also takes into account chronic kidney disease, diabetes, obesity, and other metabolic conditions people might have along with less-than-ideal heart health. The older Pooled Cohort Equations model, issued in 2013 and derived from less extensive data, advised statins for people whose risk of a cardiovascular event was 7.5% over 10 years. When the PREVENT model was applied using that 7.5% threshold, many fewer adults were deemed eligible for a statin.
The new analysis using PREVENT data calculated lowering that threshold to three different levels: a 3%, 4%, or 5% risk of a heart attack or stroke over 10 years. Settling the threshold for treatment at a 3% risk over 10 years would mean roughly the same number of people would qualify for a statin as do now. That lower 3% reflects the more robust data that PREVENT provides, study co-author Sadiya Khan, a preventive cardiologist and epidemiologist at Northwestern University who worked to develop PREVENT, told STAT.
Even the older model encouraged a discussion between doctor and patient if the 10-year risk for a heart attack or stroke was 5%, and there was also an understanding back in 2013 that patients could benefit from statins if their 10-year risk was as low as a 3%.
Statins are not without risks. Some people who take them have muscle pain, but a more pressing side effect is elevated risk for developing type 2 diabetes. Data from cholesterol treatment trials have consistently shown that over about a 10-year period, 3% of people taking statins might develop diabetes. That’s more likely in people whose blood glucose levels are closing in on the criteria for a diabetes diagnosis, Khan said. But those same people with prediabetes are also at higher risk of cardiovascular disease, raising the question of whether the benefit from taking a statin might be greater than the risk of diabetes.
Lowering the threshold from 7.5% was expected, in line with a trend toward a lower bar for treatment. Writing in a JAMA viewpoint last year, Khan and colleagues said as risk prediction tools evolve with the evidence for preventive treatments, lower-risk patients than before become candidates for drug therapy to prevent cardiovascular disease.
Gregg Fonarow, a cardiologist and professor of cardiovascular medicine and science at UCLA, took it a bit further.
The benefit of statins exceeds risk down to a 2.5% risk over 10 years, or perhaps even lower, he said, citing reanalyses of clinical trials. He was not involved in the research letter appearing in JAMA Cardiology. The lower the risk threshold being applied, he said, the larger the number of events that would be prevented.
“This new analysis provides the number of individuals in the U.S. that would be eligible for statin treatment at different risk thresholds,” he told STAT in an email. “This information will be very helpful in reformulating guidelines and efforts to reduce preventable cardiovascular events.”
A guideline from the American Heart Association and the American College of Cardiology is expected in the spring.
Keeping the number of people who might benefit the same as before, if the AHA/ACC adopt the threshold, was not the intent of the researchers, co-author Khan said.
“What we wanted to do here was really show what is the risk crosswalk like if you have a PREVENT score of 3% or 4% or 5%, how does that compare to the old risk threshold of 7.5% with the less accurate tool, and just try to put some data behind what does that look like in the U.S. population,” she said. “Because the PREVENT equations use more contemporary data, the risk estimate that we get is lower than the Pooled Cohort Equations. And I think we were really interested in making sure that we right-size the risk.”
The PCE calculator has long been widely criticized for overestimating risk, but it was more advanced than using just LDL (the “bad”) cholesterol numbers to decide who might be a candidate for a statin. Since statins were introduced in the 1980s, randomized clinical trials have demonstrated that when statins are combined with lifestyle modification, they can lower this risk of events by 25 to 40%. And they cost as little as $40 a year.
Jeremy Sussman, a primary care physician at the VA Ann Arbor Healthcare System, expressed concern that a threshold as low as 3% over 10 years might lead to more diabetes caused than heart attacks prevented. He did not participate in the new research.
“We do not necessarily want everyone on them. We want the right people on them,” he told STAT about statins. “That said, these are wonder drugs. The right number is a pretty large number. There are a lot of Americans who would benefit. And so what we want to do is find the threshold where the benefit is just about worth it. And that’s an inherently hard and inherently subjective question.”
Khan said the idea behind the risk estimation is to make sure the right people are getting a statin, independent of how many are getting a statin now.
“The bottom line is it’s just the math and making sure that we understand the risk and define who is eligible for statins based on who’s going to benefit,” she said.
Khan, Fonarow, and Sussman see the eventual guideline as part of conversations between doctor and patient that take individual needs and wishes into account.
“There are some circumstances for which the answer is obvious: The person who had a heart attack should be on a statin,” Sussman said. “At a certain point, what is a benefit that’s real but so small it’s not worth it? It’s a combination of complex science, but also subjective human values.”
STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
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