PREVENT Risk Calculator Means Fewer Patients on Statins, Antihypertensives

Dropping the current calculator for atherosclerotic cardiovascular disease (ASCVD) risk assessment—the pooled cohort equations (PCEs)—and adopting the American Heart Association’s PREVENT calculator would reclassify more than half of patients into a lower-risk category, according to a new study published this week.

Investigators also estimated that more than 14 million US adults would no longer be eligible for statin therapy with the PREVENT risk-assessment tool and 2.6 million adults would not be eligible for antihypertensive medications.

“We had the sense that any change in the way we define risk and who is at risk would have a sizable impact on related clinical decisions,” lead researcher James Diao, MD, MPhil (Brigham and Women’s Hospital/Harvard Medical School, Boston, MA), told TCTMD. “We were really struck by several changes with the new risk equation, most of all, this recalibration of risk where risk estimates across the board would decrease by almost half.”

The 2018 guidelines for managing cholesterol and 2019 guidelines for primary prevention  use the PCEs to help stratify patient risk and to guide treatment decisions. The PREVENT calculator, developed from a larger, more diverse population, is an update to the PCEs, which were first released in 2013 to estimate the 10-year risk of ASCVD. The PCEs have been criticized in the past for overestimating patient risk and being less accurate in certain groups, such as Asian and Hispanic adults, who were underrepresented in the older datasets used to develop the calculator. 

The PREVENT equations capture a spectrum of cardiovascular, kidney, and metabolic risk by factoring in renal function and statin use, as well other optional variables such as hemoglobin A1c, urinary albumin-to-creatinine ratio, and the social deprivation index. They also provide estimates of the 10- and 30-year risks of MI, stroke, and heart failure in people as young as 30 years old.

While the PREVENT calculator has not yet been adopted by the guidelines, it’s expected to supplant the older PCEs in future iterations. 

“We were particularly interested in how the changes affect different groups, especially vulnerable populations,” said Diao. “We were also interested in the effect of incorporating kidney and metabolic factors, as well as that of extending the age range to younger adults. There are many changes happening at once, and we saw an opportunity to help pick [PREVENT] apart and provide some data to inform the general cardiology community.”

This isn’t the first study to show that switching to PREVENT would result in fewer patients treated with medications. Last month, researchers published a study showing that more than 17 million adults previously eligible for statins for primary prevention, including 4.1 million current statin users, would no longer fit criteria for the lipid-lowering therapy.

PREVENT: A Contemporary Risk Calculator

PREVENT was developed from 25 datasets that included more than 3.3 million people. It was validated in 21 additional datasets with another 3.3 million patients.

With this study, published this week in JAMA, Diao and colleagues wanted to learn how switching to PREVENT might affect changes in risk categories, eligibility for treatment, and clinical outcomes. They sampled 7,765 US adults aged 30 to 79 years (median age 53 years; 51% women) participating in the National Health and Nutrition Examination Study (NHANES) from 2011 to 2020. Of this group, 24.7% were Hispanic, 22.9% were Black, and 13.4% were Asian.

The mean 10-year risk of ASCVD in the NHANES population was 9.0% when using the PCEs but just 4.6% with the PREVENT calculator. Using PREVENT, 53.0% were downgraded to a lower-risk category while just 0.41% would be bumped into a higher-risk category.

When using the 10-year ASCVD risk threshold of 7.5% to define statin eligibility in the US, 81.8 million adults qualified for treatment using the PCEs. With PREVENT, that number falls to 67.5 million. With antihypertensive medication—eligibility was based on a 10-year predicted risk of ASCVD of 10% or higher—75.3 million would be eligible for treatment with the PCEs, compared with 72.7 million when assessing risk using PREVENT.

The researchers estimated that moving patients off statins with PREVENT could lead to 77,000 additional ASCVD events and 57,800 fewer patients with new-onset diabetes, a known side effect of statin therapy. With fewer patients eligible for antihypertensive medication, researchers estimate it would lead to an additional 31,600 adverse events. After accounting for multiplicity, the shift to PREVENT would result in an estimated 107,000 additional ASCVD events, say researchers.

Diao said the point of this analysis was not to hold up the PCEs as the gold standard.

“The PREVENT equations are a major advance for cardiovascular risk prediction,” said Diao. “There are several issues with the pooled cohort equations that have been known since their release, including the overestimation of risk and development from less diverse populations.” Additionally, PCEs fail to account for people who identify as neither Black nor white and don’t account for kidney-metabolic factors that are well known to be related to cardiovascular risk.

Switching to PREVENT affected treatment eligibility for men more than women and people in their 50s and 60s compared with other age groups. With the removal of race from the PREVENT risk calculator, it’s no surprise that Black individuals were more likely to be affected by the switch, said Diao, but he noted the effect was a lot smaller than for other subgroups divided by such things as age and sex. People most affected by the switch to PREVENT were those hovering near thresholds for initiating statin or antihypertensive medications, he said.

Right Patients, Right Drugs

Amit Khera, MD (UT Southwestern Medical Center, Dallas, TX), a preventive cardiologist not involved in the study, said this analysis and others like it are necessary because the risk equations are intended for broad public use. Knowing the implications of using one or the other is crucial, he said.

The PCEs, he added, were widely known to overestimate risk, so adopting the PREVENT calculator—which is right sizing the patient’s risk—would be expected to result in fewer people treated with statins and other preventive therapies.

“Whenever you treat less, there's going to be more events,” Khera told TCTMD. “If we use an extreme example, the alternative is to treat everyone in the US population with statins. I’m not advocating for that, but if you did, and then compared [outcomes] to the pooled cohort equation, the pooled cohort equation would ‘result in more deaths’ because you stopped treating some people.”

Blanket statin use would translate into an excessively high number needed to treat to prevent a single cardiovascular event, though.

“This is a tricky calculation and it’s why we really need to think about it from the patient's perspective, to think about the number needed to treat, and [to think about] the value and risks and benefits of treatment,” said Khera. “That’s where these calculators come in, to help in those conversations. And [PREVENT], at least as best as we can tell, seems to be more accurate.”

Preventive cardiologist Sadiya Khan, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who led the development and validation of the AHA’s PREVENT calculator, believes that what’s been overlooked in current discussions about the new risk-assessment tool is that the goal is not to have the largest number of patients on medication, but “instead the right number of people on the right therapies” to prevent ASCVD.

“This, fundamentally, requires a more accurate model,” she told TCTMD. “So, we should be asking which is the best model for our patients and then we should determine what is the right threshold for treatment.”

Diao said their analysis is dependent on the thresholds used for starting therapy, and while the PCEs recommend statins for those with a 10-year ASCVD risk of 7.5% or greater, there’s no guarantee that if PREVENT is adopted the guidelines would use the same threshold.

“If it's the case that the new guidelines recommend a more liberal threshold, say 5.0% instead of 7.5%, then most of these projected outcomes won't end up happening,” he said. “The number of people who are eligible for preventive medications could go down by a lot less, or not go down at all, maybe even increase—it all depends on where they draw the new treatment thresholds.”

In an editorial, Jelani Grant, MD, Chiadi Ndumele, MD, PhD, and Seth Martin, MD (Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Baltimore, MD), write that given the safety of statins, a lower ASCVD risk threshold could be justified with future guidelines that adopt PREVENT.

“It must also be acknowledged that there is no perfect risk estimation equation,” they write. “These equations provide a starting point for risk discussions and shared decision-making in the primary prevention setting. Further risk assessment via risk-enhancing factors and arterial imaging can help tailor individual treatment plans.”

In an accompanying viewpoint, Khan, along with Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine), point to data from the Cholesterol Treatment Trialists showing that there is a benefit to starting statin therapy across the risk spectrum, including those with 5-year risk of less than 5%. Even the current cholesterol guidelines recommend a physician-patient discussion about the potential for treatment for those with a 10-year risk of ASCVD of 5%.