ACC/AHA ‘Very High Risk’ Criteria Only Modestly Predict Recurrent Events

(UPDATED) The American College of Cardiology/American Heart Association (ACC/AHA) criteria to identify vascular patients at the highest risk for recurrent cardiovascular events appears to have limited discriminative power for predicting recurrent cardiovascular events, according to the results of a new study.

In an analysis of patients with a history of atherosclerosis in the Second Manifestations of Arterial Disease (SMART) study and Reduction of Atherothrombosis for Continued Health (REACH) registry, the C-statistic for identifying very high-risk patients using the ACC/AHA criteria was 0.54 and 0.55, respectively.  

“Translating that for clinical readers, 0.5 would be like flipping a coin,” Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), one of the study investigators, told TCTMD. “It’s a little bit better than flipping a coin, but it’s not a lot better.”

Although the European Society of Cardiology (ESC) classifies all patients with a history of cardiovascular disease as very high risk for recurrent events, the older ACC/AHA clinical guidelines had reserved this designation for patients with a history of cardiovascular disease who also have diabetes, dyslipidemia, are current smokers, or have evidence of progressive coronary artery disease.

Identifying these very high-risk patients, which was defined as a 10-year risk for recurrent cardiovascular events ≥ 30%, is important as physicians can consider more intensive lifestyle interventions or further LDL-lowering therapies, such as the novel yet expensive PCSK9 inhibitors, according to the investigators. 

“Every doctor knows there are high-risk patients out there, but the challenge is identifying them before the fact,” said Bhatt. “That is identifying them before something bad happens in terms of an ischemic event.”

Modest Ability to Predict Recurrent Events

For their study published March 28, 2017, in the European Heart Journal, the researchers, led by Johanneke van den Berg, MD (University Medical Center, Utrecht, the Netherlands), included 7,216 participants in the SMART study with a history or recent diagnosis of atherosclerotic arterial disease. In addition, they included 48,322 patients with a history of atherosclerosis participating in the REACH registry.

In the SMART cohort, after a median follow-up of 6.5 years, the incidence of recurrent major adverse cardiovascular events was 2.4 per 100 person-years. Among the 57% of patients who met the ACC/AHA criteria for very high risk, the incidence of recurrent events was 2.7 per 100 person-years. In REACH, after a median follow-up of 1.8 years, the recurrent MACE rate was 5.1 per 100 person-years. In the 64% of patients considered very high risk by ACC/AHA standards, the MACE rate was 5.9 per 100 person-years.

In both SMART and REACH, the incidence of recurrent events was significantly higher among patients at very high risk than in those not meeting the ACC/AHA criteria. Overall, the highest incidence of recurrent events was observed in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73m2 and in those with polyvascular disease.  

The C-statistics were highest for the presence of polyvascular disease (0.56 and 0.58 in REACH and SMART, respectively), age greater than 70 years (0.55 and 0.58 in REACH and SMART, respectively). In both REACH and SMART, the C-statistic associated with an eGFR less than 45 mL/min/1.73m2 was 0.54. 

Even these risk factors—polyvascular disease, age greater than 70 years, and kidney disease—didn’t “perform spectacularly either,” said Bhatt. “I think the real message is that it’s challenging to identify patients who are very high risk, even though both these cohorts, REACH and SMART, had a lot of very-high-risk patients as assessed by the actual event rates,” he said. “The ability at baseline to predict who would go on to have events is really rather modest.”

To TCTMD, Bhatt said that despite the limited ability of the ACC/AHA very-high-risk criteria to predict recurrent clinical events, the criteria at least force clinicians to think about risk when prescribing and monitoring medical therapy. While smoking status, diabetes, dyslipidemia, and coronary disease progression might be on a physician’s radar, clinicians might overlook kidney function and polyvascular disease, particularly peripheral vascular disease, as risk factors, he said.

All Patients With CVD Get a High-Intensity Statin   

Sanjay Kaul, MD (Cedars Sinai Medical Center, Los Angeles, CA), said the very-high-risk designation for patients with established cardiovascular disease is no longer used in the 2013 ACC/AHA clinical guidelines for the treatment of elevated cholesterol. For patients with atherosclerotic cardiovascular disease, the guidelines recommend high-intensity statin therapy for all, while the very-high-risk designation is a holdover from the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III, which had recommended such patients be treated to an LDL cholesterol target of less than 70 mg/dL.

That said, the study addresses a common scenario, Kaul commented. “For people with established cardiovascular disease, not all of them are at high risk for recurrent events,” he told TCTMD. “There’s variation in the frequency of recurrence.”

As the researchers pointed out, vascular patients at the highest risk might benefit from additional therapy, including treatment with the expensive PCSK9 inhibitors evolocumab (Repatha, Amgen) and alirocumab (Praluent, Regeneron/Sanofi).

In March, the large cardiovascular morbidity and mortality FOURIER trial showed that treatment with the evolocumab resulted in a 15% relative reduction in clinical events when added to statin therapy in patients with stable atherosclerotic disease. Kaul said he would be interested to learn how many patients in the trial would be classified as being at very high risk for recurrent events—regardless of the criteria used—and the treatment effect in this group of patients.

“If the treatment effect was large, much better than the disappointing 15% relative risk reduction we saw, then you could make a case that the cost would not be so prohibitive,” said Kaul. “I would say, though, without a mortality advantage, it is difficult to accept $14,000 per year for a therapy. It would have to reduce the absolute risk by at least 3% to 4% per year—30% to 40% risk reduction—for me to consider the price of PCSK9s as acceptable.”

Regarding the inability of the very-high-risk criteria to accurately discriminate risk, Kaul noted the ACC/AHA standards were primarily directed for use in patients without established cardiovascular disease, the primary-prevention population. With SMART and REACH, the researchers attempted to test the criteria’s ability to identify those at highest risk within two secondary prevention cohorts.