In high-risk younger patients, cholesterol guideline suitability questioned
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A new paper has questioned whether the 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol appropriately identifies younger high-risk patients as candidates for statin therapy.
According to the study published in the Journal of the American College of Cardiology, the guideline does not flag most younger patients with premature MI as candidates for statin therapy before their event, and most patients with premature MI were not recommended by the guideline for intensive lipid management after MI.
However, two authors of the guideline said the study investigators may have misinterpreted how the guideline addresses younger patients at high risk.
Michel Zeitouni, MD, MSc, second-year fellow in the Duke Clinical Research Institute at Duke University School of Medicine and one of the authors of the JACC paper, told Cardiology Today that “This failure to identify young patients at risk occurs despite them having a high proportion of concomitant risk factors and risk enhancers such [as] family history of CAD, metabolic syndrome, obesity and high LDL-C and triglyceride levels. A better implementation of these specific risk factors in the algorithm to identify and treat patients with statins could improve cardiovascular prevention of young individuals at risk.”
Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said in an interview that the study “helps inform us about something that many physician-scientists have known and been concerned about for some time. The guidelines are suboptimal because they require you to be older in order to reach the risk thresholds required for treatment. There are many young people, as pointed out in the manuscript, that have myocardial infarctions. They often have multiple risk factors, but if you use the Pooled Cohort Risk Equation approach, their risk is reported to be very low. The people that would have the most to gain by being treated are not.”
Carl E. Orringer, MD, associate professor of clinical medicine at University of Miami Miller School of Medicine and one of the authors of the 2018 cholesterol guideline, told Cardiology Today that the study authors may have misunderstood the recommendations for younger adults.
“It is clear that identification of younger individuals, particularly those less than 40 years of age, at risk for myocardial infarction is less evidence-based than that for older individuals, and therefore, more fraught with uncertainty,” he said. “However, the authors of this paper unfortunately misinterpreted the recommendations for ASCVD risk assessment that were stated in the 2018 guideline. They stated that those at a 10-year ASCVD risk of 7.5% or greater had a class Ia recommendation for a statin only if risk-enhancing factors were present. This is in fact an error since the text of the guideline clearly states that initiation of statin therapy in those with a 10-year risk of 7.5% is a class Ia recommendation, and that the risk-enhancing factors are to be used to inform the clinician-patient risk discussion about statin initiation. However, their absence does not change the strength of recommendation for statin initiation.”
Neil J. Stone, MD, MACP, FACC, FAHA, vice chair of the committee that wrote the 2018 guideline and Bonow Professor of Medicine in Preventive Cardiology at Northwestern University Feinberg School of Medicine, said in an interview that many younger people with MI smoke, and focused risk discussion to improve high risk behaviors was specifically recommended. Also, he said, the guideline recommends statin therapy for children aged 10 years or older with or suspected of having familial hypercholesterolemia. However, the risk enhancers from the guideline were not characterized correctly in the JACC analysis, he said.
Also, he said, “The authors were incorrect in stating that in 2018, an enhancing factor was required in those adults aged 40 to 75 years with 10-year ASCVD risk of 7.5% to 19.9% to initiate statin therapy. Risk discussions were recommended but enhancing factors were not required. Enhancing factors personalize the risk decision and use of a coronary artery calcium score is advised if a risk decision is uncertain.”
Patients with first MI
For the retrospective observational study published in JACC, researchers analyzed data from 6,639 patients who presented with a first MI between 1995 and 2012. Several clinical variables were collected at admission including race, age, CV risk factors, BMI and BP.
Researchers determined statin therapy eligibility with criteria from the 2013 and 2018 AHA/ACC guidelines.
“Premature cardiovascular disease remains hard to prevent because the traditional risk models we use aren’t as sensitive to identify young adults compared with older adults,” Ann Marie Navar, MD, PhD, associate professor of medicine at Duke University School of Medicine, affiliate faculty member of Duke- Margolis Center for Health Policy, member in the Duke Clinical Research Institute and Cardiology Today Next Gen Innovator, said in an interview. “We were hopeful that the incorporation of more risk enhancers in the 2018 guidelines would improve our ability to identify young adults, and so we undertook this study to see how the new guidelines are performing.”
The 2018 guidelines were also used to determine potential eligibility for lipid-lowering therapies in patients considered very high risk by assessing a composite of recurrent MI, all-cause death or stroke. These rates in patients considered very high risk were compared with those who were not in this risk category.
Among the cohort, 41% were younger than 55 years (the younger group), 35% were aged 55 to 65 years (the middle-aged group) and 24% were aged 66 to 75 years (the older group).
Compared with the other age groups, younger patients were more likely to be smokers, to be obese, to have higher LDL and to have metabolic syndrome, according to the researchers.
Younger patients before their MI were less likely to meet guideline indications for statin therapy under the 2013 guideline (42.9% vs. 70% vs. 82.5%, respectively; P < .001) and the 2018 guideline (39.4% vs. 59.5% vs. 77.4%, respectively; P < .001) compared with middle-age and older patients.
Compared with the 2013 guideline, the 2018 guideline identified fewer younger patients who were eligible for statin therapy at the time of their MI (P < .01; Graphic).
Younger patients did not meet the criteria for intensive secondary prevention lipid-lowering therapy as often as the other age groups (28.3% vs. 40% vs. 81.4%, respectively; P < .001).
Compared with patients who did not meet very high risk criteria, patients younger than 55 years who met very high-risk criteria had elevated risk for major adverse CV events over a median follow-up of 8 years (44.6% vs. 25.9%; HR = 2.09; 95% CI, 1.82-2.41). The same was true in the middle-aged (48.1% vs. 28.5%; HR = 1.97; 95% CI, 1.72-2.27) and older groups (52.6% vs. 40.8%; HR = 1.51; 95% CI, 1.23-1.84).
Adequacy of classic approach
“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” Navar said in an interview. “While awaiting more definitive research, we should, at minimum, be using all the tools at our disposal, including broader use of CAC scoring to identify young people who may benefit from statin therapy. One of those tools, which is guideline-based, is CAC scoring, which has been shown to improve risk prediction. Unfortunately, a CAC score is only useful if we can get the test done, and most insurances don’t cover it. We also need to be careful to screen for the presence of the risk enhancers the guidelines [show] us such as inflammatory disease, family history and women-specific risk factors to make sure we aren’t missing important high-risk groups.”
However, Orringer said that misinterpreting the guideline has led to errors in these conclusions.
“Unfortunately, the authors also erroneously stated that the absence of risk-enhancing factors downgrades the strength of recommendation for those with a 10-year risk of 7.5% or greater to class IIa, a statement that does not appear anywhere in the guideline,” Orringer said.
The goal, Nissen said in an interview, should be to “identify people who are outliers with high LDLs and not base our decision on their 10-year risk but on their lifetime risk. And treat more of them. The authors are giving us some ammunition to push that approach. Unfortunately, we are undertreating with statins in America, and I think liberalizing the guidelines is needed.
- Reference:
- Zeitouni M, et al. J Am Coll Cardiol. 2020;doi:10. 1016/j.jacc.2020.06.030.
- For more information:
- Ann Marie Navar, MD, PhD, can be reached at ann.navar@duke.edu; Twitter: @annmarienavar.
- Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.
- Carl E. Orringer, MD, can be reached at carl.orringer@gmail.com.
- Neil J. Stone, MD, MACP, FACC, FAHA, can be reached at nstonemd1@gmail.com.
- Michel Zeitouni, MD, MSc, can be reached at michel.zeitouni@duke.edu; Twitter: @michelzedbay.
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