Cholesterol guideline suitability questioned in younger patients with, at risk for MI
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The 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol does not flag most younger patients with premature MI as candidates for statin therapy before their event, researchers found.
In addition, most patients with premature MI were not recommended by the guideline for intensive lipid management after MI, according to the study published in the Journal of the American College of Cardiology.
“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,” Michel Zeitouni, MD, MSc, second-year fellow in the Duke Clinical Research Institute at Duke University School of Medicine, told Healio. “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, told Healio 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 Healio 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.”
Patients with first MI
In this retrospective observational study, 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, told Healio. “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 old (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 groups, younger patients were more likely to be smokers (younger group, 51.8%; middle-aged group, 38.3%; older group, 21.6%; P for trend < .001) and have obesity (41.6% vs. 33.7% vs. 30.9%, respectively; P for trend < .001). In addition, younger patients were also more likely to have higher LDL (117 mg/dL vs. 107 mg/dL vs. 103 mg/dL, respectively; P for trend < .001) and have metabolic syndrome (21% vs. 18.6% vs. 17.3%, respectively; P < .002).
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 (46.4% vs. 56.7%; P < .01).
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 of age 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).
“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 told Healio. “Thus, these unfortunate errors result in conclusions that are not supported by the … guideline.”
Zeitouni told Healio that more research is needed focused on this younger adult population. “With the epidemy of metabolic syndrome, obesity and sedentary lifestyle, we can expect premature CAD to continue to increase among the population,” he said. “There is a need to develop trials of cardiovascular prevention specific to these patients, and identify and implement multimodal risk enhancers: social deprivation, genetics, biomarkers such as Lp(a) or ApoB levels and assessments of infra-clinical inflammation.”
The goal, Nissen told Healio, 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."
Greater prevention efforts needed
In a related editorial, Ron Blankstein, MD, MSCCT, FASNC, FACC, FASPC, director of cardiac computed tomography, associate director of the cardiovascular imaging program and associate physician of preventive cardiology at Brigham and Women’s Hospital, associate professor of medicine and radiology at Harvard Medical School, and Avinainder Singh, MD, MMSc, resident at Yale School of Medicine, wrote, “It is important to recognize that certain risk factors may be particularly important among young individuals including tobacco use, low high-density lipoprotein cholesterol, obesity and substance abuse. When considering these factors, it is apparent that there are many more opportunities to reduce the risk of MI beyond just cholesterol-lowering agents. Ultimately, greater primordial and primary prevention efforts are needed. If our goal is to achieve the greatest possible reduction in cardiovascular events, we should not miss any opportunities to improve prevention.”
Reference:
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.
Michel Zeitouni, MD, MSc, can be reached at michel.zeitouni@duke.edu; Twitter: @michelzedbay.
Perspective
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Neil J. Stone, MD, MACP, FACC, FAHA
Identifying those at risk for premature CHD in young adults continues to be an important challenge for guidelines. Although the analysis by Zeitouni and colleagues is useful for highlighting certain limitations in early prevention of MI, the following points should be noted.
Young adults were more frequently smokers in the Zeitouni, et al. analysis. The 2018 guidelines did not ignore them. In the section on young adults, they recommended lifetime risk assessment and “a focused risk discussion designed to improve high-risk lifestyle behaviors including tobacco use, sedentary lifestyle and/or poor diet.” Since we have no randomized controlled trial data on statins for those aged 20 to 39 years, more intensive lifestyle counseling on tobacco and lifestyle as recommended could make a difference. The value of smoking cessation after a premature MI suggests the usefulness of more intensive lifestyle counseling as recommended by guidelines before the MI (Biery DW, et al. JAMA Netw Open. 2020;doi:10.1001/jamanetworkopen.2020.9649.).
The authors do not make it clear that the children and adolescents section of the guidelines did encourage statin therapy in children and adolescents 10 years of age or older with an LDL level persistently 190 mg/dL or higher (≥ 4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with familial hypercholesterolemia (IIA recommendation). Earlier recognition of FH and attention to adequate treatment as recommended by the guidelines should reduce CHD rates in young adults (Singh A, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.02.059.).
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 risk of 7.5% to 19.9% to initiate statin therapy. The IA recommendation was “in adults at intermediate-risk, statin therapy reduces risk of ASCVD, and in the context of a risk discussion, if a decision is made for statin therapy, a moderate-intensity statin should be recommended.” 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.
There were problems with the definition of risk enhancers used in the analysis. Not all were measured, and the criteria for metabolic syndrome were incorrect. The guidelines used a fasting triglyceride of 150 mg/dL or higher as one of its criteria, not 175 mg/dL. The latter, if persistent and non-fasting, was a risk enhancer separate from the metabolic syndrome.
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