Source/Disclosures
Disclosures: Mortensen reports no relevant financial disclosures. Gencer reports he received grant support from Athemis Foundations, Eugenio Litta and Geneva University Hospitals. Raal reports he received grants, honoraria or consultant fees from Amgen, Novartis, Regeneron, Sanofi and The Medicines Company. Mohamed reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.
November 10, 2020
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High LDL elevates CV risk in older patients; primary prevention may be appropriate

Source/Disclosures
Disclosures: Mortensen reports no relevant financial disclosures. Gencer reports he received grant support from Athemis Foundations, Eugenio Litta and Geneva University Hospitals. Raal reports he received grants, honoraria or consultant fees from Amgen, Novartis, Regeneron, Sanofi and The Medicines Company. Mohamed reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.
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High LDL in older patients may confer increased risk for atherosclerotic CVD and MI, and therefore this population may benefit from targeted LDL-lowering therapies, according to two studies published in The Lancet.

Older patients and high LDL

For one analysis, investigators included 91,131 individuals aged 20 to 100 years from the Copenhagen General Population Study who had high LDL, no ASCVD or diabetes at baseline and no statin use, with the goal to assess risk for MI and ASCVD.

Old man taking pill
Source: Adobe Stock.

During a mean 7.7 years of follow-up, 1,515 participants experienced their first MI and 3,389 developed ASCVD.

Researchers observed that per every 1 mmol/L increase in LDL, all age groups experienced increased risk for MI (HR = 1.34; 95% CI, 1.27-1.41) and ASCVD (HR = 1.16; 95% CI 1.12-1.21), and that the trends were most pronounced in people aged 70 to 100 years.

Compared with people aged 80 to 100 years with LDL < 3 mmol/L, those aged 80 to 100 years with LDL 5 mmol/L or more experienced greater risk for MI (HR = 2.99; 95% CI, 1.71-5.23) and ASCVD (HR = 1.9; 95% CI, 1.27-2.83).

Similar increased risk was observed within the other age groups; however, as both LDL levels and age increased, so did the risk for MI and ASCVD.

According to the study, the highest event rates were recorded among those aged 80 to 100 years with LDL of 5 mmol/L or more for both MI (13.2 events per 1,000 person-years) and ASCVD (37.1 events per 1,000 person-years).

“Besides increased life expectancy, evidence suggests that older individuals have become healthier, with compression of morbidity — ie, a shorter time of life is lived with disabling comorbidity due to postponement of disease onset,” Martin Bødtker Mortensen, MD, PhD, of the department of cardiological medicine at Aarhus University in Denmark, and colleagues wrote. “These favorable changes could account for why elevated LDL cholesterol is associated with increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70-100 years in contemporary, but not in historic, populations.”

Moreover, the event rate for MI was nearly four times higher among individuals aged 80 to 100 years with LDL of 5 mmol/L or higher vs. participants aged 20 to 69 years with similar LDL (adjusted HR = 3.7; 95% CI, 1.6-8.8).

Investigators calculated that the number needed to treat with LDL-lowering therapy in 5 years to prevent one MI was:

  • 80 for individuals aged 80 to 100 years;
  • 145 for those aged 70 to 79 years;
  • 261 for those aged 60 to 69 years;
  • 439 for those aged 50 to 59 years; and
  • 1,107 for those aged 20 to 49 years.

Additionally, the number needed to treat in 5 years to prevent one ASCVD event was:

  • 42 for individuals aged 80 to 100 years;
  • 88 for those aged 70 to 79 years;
  • 164 for those aged 60 to 69 years;
  • 345 for those aged 50 to 59 years; and
  • 769 for those aged 20 to 49 years.

“These data are of importance for primary prevention strategies and guidelines aimed at managing and reducing atherosclerotic cardiovascular disease in the growing older population,” the researchers wrote. “However, efficacy and safety of statin therapy in individuals aged 70 to 100 years needs to be tested directly in randomized trials. Specifically, statin­associated adverse events might increase with aging due to impaired statin metabolism from age-related declines in renal and hepatic function and higher numbers of concomitant drugs with potential drug-drug interactions.”

Benefit of LDL-lowering therapies

In another study, Baris Gencer, MD, research fellow in medicine at Brigham and Women’s Hospital, and colleagues conducted a meta-analysis of six randomized controlled trials to assess the effect of LDL-lowering drugs, as recommended by the 2018 American College of Cardiology and American Heart Association guidelines, on CV outcomes in patients aged at least 75 years. For the analysis, investigators analyzed the risk ratio for major vascular events, including CV death, MI or other ACS, stroke or coronary revascularization, for each 1-mmol/L reduction in LDL.

Overall, 54.7% of participants were from statin trials, 28.9% were from ezetimibe trials and 16.4% were from PCSK9 inhibitor trials.

Researchers observed that LDL lowering significantly reduced the risk for major vascular events in older patients by approximately 26% per 1 mmol/L reduction in LDL (RR = 0.74; 95% CI, 0.61-0.89), a rate of risk reduction similar to that in patients younger than 75 years (RR = 0.85; 95% CI, 0.78-0.92; P for interaction = .37).

Among older patients, the risk for major vascular events was not statistically different between those treated with statins (RR = 0.82; 95% CI, 0.73-0.91) and those treated with nonstatin therapies (RR = 0.67; 95% CI. 0.47-0.95; P for interaction = .64).

Moreover, older patients derived benefit of LDL lowering in each component of the composite outcome of major vascular events, including CV death (RR = 0.85; 95% CI, 0.74-0.98), MI (RR = 0.8; 95% CI, 0.71-0.9), stroke (RR = 0.73; 95% CI, 0.61-0.87) and coronary revascularization (RR = 0.8; 0.66-0.96).

“In addition to showing that lipid­lowering therapies reduce mortality and morbidity in older patients, we also found no offsetting safety concerns,” Gencer and colleagues wrote. “Some concerns related to hemorrhagic stroke were considered as a potential barrier for LDL-cholesterol lowering in older patients with statins. In the [Cholesterol Treatment Trialists’ Collaboration] meta­analysis, no data were presented for statin treatment with respect to hemorrhagic stroke in older patients. However, in the nonstatin trials, no signal has been observed, nor was an excess of either new­onset diabetes or neurocognitive adverse events shown in older patients with nonstatin treatment.”

In a related editorial, Frederick J. Raal, MBBCh, MMed, PhD, FCP(SA), FRCPC, MRCP, MRCP, FRCPC, professor of endocrinology, and Farzahna Mohamed, MB, MCh, associate lecturer of internal medicine, both at the University of the Witwatersrand in Johannesburg, wrote: “We should be looking not only at the short-term benefit with the initiation of lipid-lowering therapy or more intensive lipid-lowering in older patients for primary or secondary prevention, but also at the longer-term lifetime benefit from the much earlier initiation of lipid-lowering therapy in those at risk.

“When to start lipid-lowering therapy and the duration of therapy are probably more important than whether to start lipid-lowering therapy, particularly for the primary prevention of cardiovascular disease in older patients, for whom further evidence is required,” the editorial authors wrote.

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