Two complimentary papers presented at the American Heart Association Scientific Sessions 2020 Virtual meeting, and published back to back in the Lancet [1,2], showed strong evidence that individuals aged over 70 years benefit at least as much as younger people from cholesterol-lowering therapies. Physician’s Weekly interviews the lead investigator from one of these studies, Børge Nordestgaard, MD, DMSc, Clinical Professor of Genetic Epidemiology at the University of Copenhagen, Denmark.


Cumulative burden of LDL-cholesterol with age

In one of the papers, a Danish primary prevention cohort of 91,131 people aged 70-100 years who lived in Copenhagen, Denmark, and who did not have atheroeriosclerotic cardiovascular disease (ASCVD) or diabetes, and were not taking statins, were observed for a mean follow-up of 7.7 years [1]. During that period, 1,515 participants experienced a first myocardial infarction, and a total of 3,389 individuals developed atherosclerotic cardiovascular disease. After multivariate adjustment, the risk of having a myocardial infarction (MI) and ASCVD events increased per 1.0 mmol/L increase in low-density lipoprotein (LDL) cholesterol in the cohort (hazard ratio [HR] 1.34), including those aged 80 to 100 (HR 1.28). Other age cohorts showed nearly identical data , such as ages 70 to 79 (HR 1.25), 60 to 69 (HR 1.29), or 50 to 59 (HR 1.28). The data clearly suggest that increased LDL cholesterol is still linked to subsequent myocardial infarction (MI) and ASCVD events in all-age individuals without baseline ASCVD or diabetes.

Nevertheless, the absolute risk of MI and ASCVD did increase with age. For example, individuals aged 80-100 years experienced 2.5 more ASCVD events per 1,000 person-years with every 1.0 mmol/L increase in LDL cholesterol, whereas people age 20-49 years experienced 0.6 more ASCVD events per 1,000 person-years. The authors point out that it is likely to be the cumulative burden of LDL cholesterol acquired over a lifetime that results in the progressive increase in risk for MI and ASCVD with age. The take-home message is that high LDL cholesterol in healthy people no matter their age requires lipid-lowering therapy, because it is associated with a substantially higher risk of developing MI and ASCVD.

Lowering LDL cholesterol in older patients is beneficial

In a complementary systematic review and meta-analysis published back-to-back with the Danish study [2], lipid-lowering was shown to be as effective in reducing cardiovascular events In patients aged ≥75 years as it was in younger patients. The results should  collectively strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.

Presented at the Scientific Sessions by Dr. Baris Gencer (Brigham and Women’s Hospital, USA), the meta-analysis included a total of 244,090 patients from 29 trials, 21,492 (8.8%) of whom were aged at least 75 years. Of those, 11,750 (54.7%) were from statin trials, 6,209 (28.9%) from ezetimibe trials, and 3,533 (16.4%) from PCSK9 inhibitor trials. Median follow-up was between 2.2 years and 6.0 years.

The results showed that reducing LDL cholesterol significantly ameliorated the risk of major vascular events (n=3,519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0.74; 95% CI 0.61–0.89; P=0.0019), with no statistically significant difference with the risk reduction in patients <75 years (RR 0.85; 95% CI 0.78–0.92; Pinteraction=0.37). Among older patients, relative risks were not statistically different for statin (RR 0.82; 95% CI 0.73–0.91) and non-statin treatment (RR 0.67; 95% CI 0.47–0.95; Pinteraction=0.64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite endpoint, including cardiovascular death (RR 0.85; 95% CI 0.74–0.98), myocardial infarction (RR 0.80; 95% CI 0.71–0.90), stroke (RR 0.73; 95% CI 0.61–0.87), and coronary revascularization (RR 0.80; 95% CI 0.66–0.96). Collectively, these 2 studies contradict the older data suggesting that LDL cholesterol levels in older individuals did not need to be treated.

When asked by Physician’s Weekly to contextualize these studies with regard to historical literature, Prof. Nordestgaard replied: “These results have now become extremely relevant in many high-income countries because we have a growing population of people above age 70 that actually have a long life expectancy. By preventing cardiovascular disease, the elderly can live a healthy active life, until they die from some other reason. “

Why were these findings novel?

“The question of whether the elderly have the same was originally addressed in historical studies, which recruited people 30 to 40 years ago. The old studies did not find that high LDL cholesterol was very important in the elderly, in contrast with what we find today. Back then, people did not live so long; life expectancy was much lower and with limited options for the treatment of comorbidities. Furthermore, preventive therapies were not very established. Today, people live much longer and health ier, with disease onset later in life. These favorable changes could account for why elevated LDL cholesterol is associated with increased risk of MI and ASCVD in individuals aged 70–100 years in contemporary, but not in historic, populations.”
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Implications

“Until now, many doctors have thought that when people live above a certain age without evident cardiovascular disease, about 70 or 75, you should not have to worry so much about managing their cholesterol anymore for primary prevention. The reasoning is, that if the individual has made it this far, higher cholesterol levels may not put them at higher risk for ASCVD or MI. However, these two new studies have shown that irrespective of your age, if your patient has high cholesterol, think about doing something to treat it and bring it down.

Previously, people generally would have used 2 arguments: we do not know if high LDL cholesterol is important in the elderly and we do not know if statins or LDL-lowering works. Now, these two studies together clearly say that people above age 70 have a high risk of CVD if they have high LDL, and the other paper says that if you reduce LDL, you reduce risk. It seems that there was a trend to actually reduce risk even more in the elderly than those below 70 or 75 in age.”

Practice-changing?

“I think Guidelines will move the age upwards. Until now, most guidelines give a strong recommendation for ages 40-75 years, and a few of the guidelines say you could treat older patients after talking with your patient. However, now it seems likely that the strong recommendation for using statins or other lipid-lowering approaches will shift in those above the ages 70-75 . Of course, also, there are some randomized trials ongoing such as the much-anticipated STAREE trial in a primary prevention cohort including ages 70 and older. If those results come out very strong, that will add strength to the guidelines.”

 

Sources

  1. Mortensen MB, Nordestgaard BG. Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70-100 years: a contemporary primary prevention cohort. Lancet. 2020 Nov 21;396(10263):1644-1652. doi: 10.1016/S0140-6736(20)32233-9. Epub 2020 Nov 10. PMID: 33186534.
  2. Gencer B, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020 Nov 9:S0140-6736(20)32332-1.